Lowering cholesterol blood levels with flavanoids

ABSTRACT

A method of effecting a cholesterol-level-decreasing effect in blood, and also pharmaceutical compositions, are both based on substituted flavanoids of the following formula, as well as their acid addition salts and quaternary ammonium derivatives: WHEREIN R1 and R2 are identical or different and can represent OH; alkoxy of one to 10 carbon atoms and if desired substituted by other moieties; tetrahydropyranyl-(2)-oxy; acyloxy of one to six carbon atoms; NO2; NH2; alkylated NH2 having one to eight carbon atoms; or acylamino of two to six carbon atoms; R3 can represent H; OH; alkyl and alkoxy of one to three carbon atoms; NH2; or Hal; R4 can represent O; H, OH; H, H; or N, NH2; R5 can represent H or R1; Hal can represent Cl; Br; or I; R2 and R5 together can also represent methylene dioxy; ethylene dioxy; or propylene dioxy; and wherein, in the 2,3-position, an additional double bond can be present.

United States Patent Kramer et al.

: Sept. 5, 1972 LOWERING CHOLESTEROL BLOOD LEVELS WITH FLAVANOlDSInventors: Josef Kramer; Klaus lrmscher, both of Darmstadt; Hans-OttoViige, Ober-Ramstadt; Herbert Halpaap, Jugenheim, all of Germany E.Merck Aktiengesellschaft, Darmstadt, Germany Filed: April 2, 1969 Appl.No.: 850,273

Related US. Application Data Division of Ser. No. 392,304, Aug. 26,1964, Pat. No. 3,450,717.

Assignee:

Foreign Application Priority Data Aug. 28, 1963 Germany ..M 57991 Oct.5, 1963 Germany ..M 58433 Jan. 18, 1964 Germany ..M 59597 March 4, 1964Germany ..M 60149 May 9, 1964 Germany ..M 60951 Primary Examiner- SamRosen Attorney-l. William Millen [57] ABSTRACT A method of effecting acholesterol-level-decteasing effect in blood, and also pharmaceuticalcompositions,

are both based on substituted flavanoids of the following formula, aswell as their acid addition salts and quaternary ammonium derivatives:

wherein R and R are identical or different and can represent OH; alkoxyof one to 10 carbon atoms and if desired substituted by other moieties;tetrahydropyranyl-(2)-oxy; acyloxy of one to six carbon atoms; N0 NHalkylated NH having one to eight carbon atoms; or acylamino of two tosix carbon atoms;

R can represent H; OH; alkyl and alkoxy of one to three carbon atoms; NHor Hal;

R, can represent 0; H, OH; H, H; or N, NH

R can represent H or R Hal can represent Cl; Br; or I;

R and R together can also represent methylene dioxy; ethylene dioxy; orpropylene dioxy; and wherein, in the 2,3-position, an additional doublebond can be present.

10 Claims, No Drawings LOWERING CHOLESTEROL BLOOD LEVELS WITH FLAVANOIDSCROSSREFERENCE TO RELATED APPLICATIONS This application is a divisionalapplication of application Ser. No. 392,304, filed Aug. 26, 1964, nowUS. Pat. No. 3,450,717, issued June 17, 1969.

This invention relates to novel substituted flavanoids, their uses, andprocesses of production.

An object of this invention, therefore, is to provide novel flavanoidderivatives.

Another object is to provide processes for the production of these novelcompounds, as well as novel intermediates therefor.

Still further objects include pharmaceutical preparations and methods ofeffecting therapeutic activity based on the novel compounds of thisinvention.

Upon further study of the specification and claims, other objects andadvantages of the present invention will become apparent.

The novel substituted flavanoids of this invention correspond to thecompounds of Formula I, as well as their acid addition salts andquaternary ammonium derivatives, as follows:

wherein:

R and R are identical or different and can represent OH; alkoxy of oneto ten carbon atoms and if desired substituted by other moieties;tetrahydropyranyl-(2)- oxy; acyloxy of one to six carbon atoms; N NHalkylated NH having one to eight carbon atoms; or acylamino of two tosix carbon atoms;

R can represent H; OH; alkyl and alkoxy of one to three carbon atoms; NHor Hal;

R, can represent 0; H,OH; H,H; or H,NH

R, can represent H or R Hal can represent Cl; Br; or I;

R and R together can also represent methylene dioxy; ethylene dioxy; orpropylene dioxy; and wherein, in the 2,3-position, an additional doublebond can be present; with the following provisions:

A. when R H, R, O, and there is a single bond connecting the2,3-position,

1. R represents CH O if the following sub-provisions are observed:

a. R is not CH O and R is neither CH O nor CH OCH O;

b. R is not HN and R is none of OH, CH O and csfi fizq;

c. R, is not OH and R is not CH 0;

2. R and R together represent methylene dioxy subject to the followingsub-provision: a. R is neither OH nor NH 3. R is H if the followingsub-provision is observed:

a. R, is neither CH O nor HN, and R is not CH O;

B. when R,'- O and there is a double bond connecting the 2,3-position.

l. R, is CH O if the following subprovision is observed: a. R is notNO,, R is not CH O, and R is neither I H nor OH; 2. R is H if thefollowing sub-provisions are observed: a. R, and R, are neither both OHnor both CH O.

and R is neither H nor OH; b. R, is not C H O, R, is neither C H O norCH O, and R is not H; c. R, and R, are not OH, and R is not CH O.

The novel flavanoids and also the compounds of for- I X-Ar X representsCHiCX -CHRaCHX or CHCH- X, represents H, OH, Hal, or amino, R to R andHal are defined as above, and wherein phenolic hydroxy groups can alsobe present in protected form;

III

wherein Z represents --CHR CHAr or CR CAr, X represents COOH, COHal, CHOH or CH Hal,

and Ar, R R R R and Hal have the abovementioned composition. A compoundof the Formula IV is treated with a reducing agent.

wherein Y represents 8 0 0 O Ar Ar Ar Ar A I E R3 R3 -R: V R;

R represents or I-I,OH, and A represents an anion of a strong acid,

Ar and R to R, are defined as above, and wherein phenolic hydroxy groupscan also be present in protected form.

In conjunction with the above processes, or independently therefrom, adouble bond in the 2,3-position is inserted into a compound of Formula Iby treatment with a dehydrogenating agent; and/or, in a compound ofFormula I, one or several of the substituents R to R are converted intoother substituents R to R in such a manner that protected hydroxyand/oramino-groups are freed by treatment with hydrolyzing and/orhydrogenolyzing agents; or free hydroxyand/or amino-groups are alkylatedor acylated by treatment with alkylating or acylating agents; or nitrogroups are reduced to amino groups. Alternatively, a keto group in the4-position is transformed into an amino group by oxime formation andsubsequent reduction, or a carboxylic acid or carboxylic acid alkylester group is transformed into a carboxylic acid amide group bytreatment with an aminating agent, if desired passing through severalstages. Likewise, in the 3-position, by treating with halogenation,oxidation, alkylation, or aminating agents, an Hal atom, or a hydroxy-,alkyl-, or amino-group can be introduced, and/or, if desired, compoundsof the Formula I are converted, by treating with acids and alkylatingagents, respectively, to their physiologically compatible acid additionsalts and quaternary ammonium compounds, respectively.

As alkoxy groups in the residues R R and/or R the following areexemplified: methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,sec. butoxy, tert. butoxy, amyloxy, isoamyloxy, hexyloxy, isohexyloxy,heptyloxy, octyloxy, nonyloxy, decyloxy, as well as allyloxy, benzyloxy,cyclopentyloxy, cyclohexyloxy; further, the aforementioned groups withadditional basic, acidic, or neutral substituents, these substituentspreferably being the following: amino; alkylated amino, such asdimethylamino, diethylamino, pyrrolidino, piperidino, morpholino;carboxy; carbalkoxy, such as carbomethoxy, carbethoxy; cyanc;carboxamido; dialkylcarboxamido, such as dimethylor diethylcarboxamido.When the alkoxy group is substituted, it is preferable that the alkoxygroup be of 1 carbon atoms in the alkoxy chain substituted by a memberof the group consisting of phenyl; amino; alkylated amino of l 9 carbonatoms; pyrrolidino; carboxy; carbalkoxy of 2 9 carbon atoms; cyano;carboxamido; dialkylcarboxarnido of 3 9 carbon atoms;pyrrolidinocarbonyl;

and (Z-hydroxyethylamino)-carbonyl. Correspondingly, suitable groups are2- dimethylaminoethoxy, Z-diethylaminoethoxy, 2-pyrrolidinoethoxy,2-piperidinoethoxy, 2- rno holinoethoxy, B-dimethylaminopropoxy, 3- dieylaminopropoxy, carboxymethoxy, carbalkoxboxarnid0)-ethoxy. In thementioned residues, additional double bonds may also be present.

In case R R and/or R represent acyloxy or acylamino groups, thepreferred acyl residues are those which are derived from carboxylicacids having up to six carbon atoms, advantageously fonnyl, acetyl,propi'onyl, butyryl, isobutyryl, valeryl, isovaleryl, caproyl, andisocaproyl. In case R and/or R represent amino groups, these can bemono-alkylated or dialkylated; preferably, the alkyl residues in oneamino group can have a total of up to 8 carbon atoms, the followinggroups being particularly preferred: methyl, ethyl, npropyl, isopropyl,n-butyl, isobutyl, amyl, hexyl, dimethyl, diethyl, di-n-propyl,diisopropyl, di-n-butyl, and/or diisobutylamino groups. The alkylresidues may also form, together with the nitrogen atom, a heterocyclicring, for example a piperidine or pyrrolidine ring.

Alkyl groups in residue R, can be the following: methyl, ethyl n-propyl,and isopropyl; alkoxy groups can be methoxy, ethoxy, n-propoxy, andisopropoxy.

The residue R most preferably represents the group R CO-CHR -O, whereinR is H or a lower alkyl, such as methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec. butyl, tert. butyl, n-arnyl, or isoamyl, and Ris OH, a lower alkoxy, such as methoxy, ethoxy, npropoxy, isopropoxy,n-butoxy, isobutoxy, sec. butoxy, tert. butoxy, n-amyloxy, isoamyloxy,n-hexyloxy, NH or alkylated amino, such as methyl-, ethyl-, n-propyl-,isopropyl-, n-butyl-, isobutyl-, amyl-, hexyl-, heptyl-, dimethyl-,methylethyl-, diethyl-, di-n-propyl-, diisopropylamino,2-hydroxyethylamino, pyrrolidino, piperidino, or morpholino.

The compounds of Formula IV particularly comprise flavylium salts, A andA flavenes, flavanols, flavanones, flavones, or flavonols which can besubstituted as mentioned above. The flavylium salts of Formula IV cancontain anions of any desired strong acids; the flavylium salts can bepresent, for example, as chlorides, bromides, iodides, perchlorates,tetrachloroferrates (III), or hydrogen sulfates.

The flavane derivatives of Formula I are obtainable bycyclization of thecompounds of Formula II. Particu larly preferred compounds of Formula IIare the chalcones (R O, X -CH ==CI-I, and C(CI-I CI-I-), furthermoretheir dihalogenides, particularly the dibromides, halohydrins, orepoxides. However, compounds of Formula II in which R represents H,I-Iare also well suited for cyclization.

The compounds of Formula II are especially amenable to cyclization toform the flavane derivatives of For-v mula I by the effect of basic oracidic catalysts: Alkalis, such as sodium hydroxide or potassiumhydroxide, sodium amide, sodium hydride, basic-reacting salts, such assodium acetate or potassium acetate, sodium carbonate or potassiumcarbonate; buffer solutions, for example those of citric acid anddisodium phosphate, or of sodium dihydrogen phosphate or potassiumdihydrogen phosphate and borax,.or of boric acid, sodium hydroxide andpotassium chloride; organic bases, such as piperidine, pyridine,tetramethyl guanidine, benzyl-trirnethylarnmoniumhydroxide; mineralacids, such as hydrochloric acid, hydrobromic acid, sulfuric acid,phosphoric acid, polyphosphoric acid; organic sulfonic acids, such astoluene-sulfonic acid or camphor-sulfonic acid; Lewis-acids,'such asaluminum chloride, zinc chloride, or tin tetrachloride.

The cyclization can be conducted in the presence of an inert solvent,such as methanol, ethanol, dioxane, tetrahydrofuran, acetic ester,acetic acid, tetralin, benzene, toluene, or it can also be carried out,if desired, in mixtures of these solvents with one another or withwater. It is also possible to use an excess of the cyclization agent asthe solvent. The cyclization takes place at room temperature and can beaccelerated by heating, if desired, up to the boiling point of the usedsolvent. The reaction time is several minutes up to several days.

The chalcones are preferably obtained by condensa tion of a2-hydroxy-acetophenone or propiophenone,

- substituted in the 5-position, with a p-substituted (or3,4-disubstituted respectively) benzaldehyde, or also they can beobtained from a p-substituted phenol and a p-substituted (and/or3,4-disubstituted) cinnamic acid derivative in the presence of aluminumchloride. It is not necessary to isolate the chalcone which is used asthe starting product; rather, it is also possible to react the2-hydroxy-acetophenone substituted in the 5-position with thesubstituted benzaldehyde and then treat the mixture directly with thecyclization agent. If the operation is carried out in the presence of anoxidation agent, preferably hydrogen peroxide at low temperature, forexample at (1., it is possible to introduce during this reaction at thesame time a hydroxy group in the 3-position of the flavane system.

By reacting chalcones of the Formula II (R,- 0, X CH =CH--) withhalogens, preferably bromine, the corresponding 0:, B-dihalogenides arearrived at, which can be converted into the halohydrins in the presenceof water, for example by treating with moist acetone. If thesehalohydrins are treated with bases, 3-hydroxyflavane derivatives areproduced, probably by way of the corresponding epoxide. Thesederivatives can also be produced directly from the dihalogenides bytreating with acetic acid/silver nitrate; the a, ,B-diacetoxychalconeproduced is saponifred by boiling with hydrochloric acid and is cyclizedto the flavanone. The 3-hydroxy-flavanone derivatives are furthermoreobtainable by reacting 2-hydroxy-phenacylhalogenides, substituted in the5-position, with substituted benzaldehydes in the presence of preferablybasic catalysts, the epoxide which is produced as an intermediate doesnot have to be isolated in this process.

The starting compounds of Formula II (R., HJ-l) can be produced bycondensation of a hydroquinone derivative, which is, if desired,etherified or esterified, with a compound of the formula Hal-CH -XAr. Itis possible to guide the reaction such that the compound of Formula IIdoes not have to be isolated. Furthermore, a compound of the formula RCHzCHRnMgHal whose phenolic hydroxy group or groups can also be presentin protected form, can be reacted with a benzaldehyde of the formulaArCl-IO to form a compound of Formula II (R.,- l-l,l-l), or a chalconeof the formula R, -oH-cmoomcan be reduced to the compound of Formula ll(R H,H) by treating with a reducing agent, such as sodium amalgam, or bysuccessive catalytic hydrogenation and reduction with a complex metalhydride.

Flavones of the Formula l (R, 0, double bond in the 2,3-position) can beobtained by cyclization of a ketone of Formula II (R O, X CR, ===CX,) orthe tautomeric form thereof. Such ketones are preferablydibenzoyl-methanes (R H, X, OH) which may, of course, also be present inthe corresponding diketo form; such compounds can be converted toflavones by splitting ofi a water molecule. This conversion can be done,for example, by heating several hours with glycerin, preferably undernitrogen, in the presence of acids, such as concentrated hydrochloricacid, hydrobromic acid, hydriodic acid, sulfuric acid, phosphoric acid,glacial acetic acid, formic acid, or mixtures thereof. Also, acidicsystems, such as glacial acetic acid/potassium acetate, or glacialacetic acid/sodium acetate can be employed, as well as phosphoruspentoxide, acetic anhydride, or potassium acetate in boiling alcohol.Preferably, heating is carried out for a to 3 hours at temperaturesaround C. The reaction actually occurs in the cold state, but in thatcase it is correspondingly slower. If this process is carried out in thepresence of an oxidation agent, for example employing a peracid, such asperformic acid inchloroform, it is possible to introduce a hydroxy groupin the 3-position simultaneously during this reaction.

It is, of course, possible to introduce substituents into thedibenzoyl-methane before the latter is cyclized. For example, amethylation at the methane carbon atom can be smoothly accomplished. Inplace of the dibenzoyl-methane, functional derivatives thereof can beused for cyclization. Thus, dibenzoyl-methane can be converted to anenamine, for example by reacting with benzylamine, which enamine can beacid hydrolized and simultaneously cyclized to flavone.

The dibenzoyl-methanes of Formula II (R H, R O, X OH) are obtainable bya series of different methods, and they do not have to be necessarilyisolated during the reaction.

For example, it is possible to condense a S-substituted2-hydroxy-acetophenone and/or propiophenone to 1,3-diketone by reactionwith a derivative of a benzoic acid of the formula ArCOOH, preferably anester of such a benzoic acid, under the customary conditions of an estercondensation. It is also possible to esterify a 5-substituted2-hydroxyacetophenone and/or propionphenone in the customary manner, forexample by reacting with a benzoic acid halogenide in the presence of abase, such as pyridine, and to convert the product obtained thereby intothe dibenzoyl-methane under the conditions of a Baker-Venkataraman-transformation (in the presence of sodium, potassium, analkali hydride, an alkali amide, an alkali carbonate, or an alkalihydroxide, preferably sodium hydroxide or potassium hydroxide in drypyridine).

If the obtained ester of the 5-substituted 2-hydroxyacetophenone and/orpropiophenone is treated with one of the above-mentioned cyclizationreactants, the desired flavone is obtained directly. This can be accom-1 ic acid derivative can also be carried out under the conditions of aKostanecki-Robinson-reaction. Here, one operates with a benzoic acidanhydride (ArCO) O in the presence of thecorresponding sodium benzoateor potassium benzoate, or in the presence of a tertiary base, such astrimethylor triethylamine, at tempera-' tures-between 120 and 200 C. andthus arrives at flavone, without the dibenzoyl-methane intermediatebeing isolated.

The dibenzoyl-methane derivatives of the Formula II (R, H, R, O, X, OH)are also obtainable bytransforming a 4-benzoyl-oxycumarin to 3-benzoyl-4hydroxy-cumarin and subsequent reaction with mineralacid, preferablyhydrochloric acid, the intermediate diketo acid (II: R COOH, R 0, X OH)beingv 'decarboxylated under the conditions of the reaction.

The cyclization of the compounds of Formula III is normally carried outaccording to the same methods as the cyclization of the compounds ofFormula II. Such compounds of Formula III in which X represents COOH arepreferably cyclized with acetyl chloride, phosphorus oxychloride,sulfuric acid, or polyphosphoric acid. Aluminum chloride or otherLewis-acids serve for the cyclization of the halogenides (III, X COHal).The acids can, of course, be com verted, before cyclization, into thecorresponding acid halogenides, for example by means of thionylchloride;

Esters of these acids can also be used for cyclization,-

under hydrolyzing conditions. It is not necessary to isolate thecompounds of Formula III which are used as starting products; rather,they can also be produced in situ. This can be done, for example, byreacting a hydroquinone derivative, which can be etherified oresterified, if desired, with a halogen compound of the formulaAr--CHHalCI-IR -X or ArCH--CI-I--X under the conditions stated above.for the cyclization of the compounds of Formula II. When operating undermild, alkaline conditions-for example by treating with an alkalialcoholatethe compounds of Formula III can be isolated, if desired.

Compounds of Formula III (Z CR =CAr-, X COOH) are obtainable, forexample, by additionof an alkali salt of a p-substituted phenol to anester of an acid of the formula ArC CCOOH and subsequent saponification,or by reacting a p-substituted phenol with an ester of an acid havingthe formula Ar- COCH COOH (Simonis-reaction; in the latter case, the'intermediate product III is normally not isolated). hydroxy groups arepresent in protected form as tetrahydropyranyl-ethers, this being donein an acidic or an alkaline medium; .in case of an alkaline cyclization,the hydroxy group is freed by subsequent brief boiling with acid.Compounds having a hydroxy group which is protected in ester form canlikewise be condensed in acidic or alkaline medium, the ester group'being saponified. Furthermore, ether groups, such as benzyl ether ormethyl ether, are suitable as blocking agents. Such ethers can be split,for example. if hydrobromic acid or hydriodic acid is used as thecyclization agent.

The flavane derivatives of Formula I are also obtainable by reduction ofcompounds of Formula IV. Such a reduction can be carried out bycatalytic hydrogenation, or by a chemical reducing agent.

Catalysts for the catalytic hydrogenation are, for example, noble metalcatalysts, nickel catalysts, and cobalt catalysts, as well ascopper-chromium oxide. The noble metal catalysts can be present ascarrier catalysts, as for example palladium on charcoal, calciumcarbonate, or strontium carbonate, as oxide catalysts, as for exampleplatinum oxide, or as finely divided metal catalysts. Nickel catalystsand cobalt catalysts are suitably used as Raney-metals; nickel can alsobe used on kieselguhr or pumice as carriers.

The hydrogenation can be conducted under ambient conditions or also atelevated temperature and/or increased pressure. Preferably, this processis conducted at pressures between 1 and 100 atmospheres and attemperatures between and +l50 C. Suitably, the reaction is carried outin the presence of a solvent, such as methanol, ethanol, isopropanol,tert. butanol, acetic acid ethyl ester, dioxane, glacial acetic acid,tetrahydrofuran, water, or mixtures thereof. In some cases, it isrecommended to add catalytic quantities of a mineral acid, for examplehydrochloric acid or sulfuric acid.

If, for purposes of hydrogenation, a compound of Formula IV with a basicnitrogen atom is employed, the free base, or also a salt of this base,can be used. During hydrogenation, precaution must be taken that the Momatic rings are not likewise attacked. Preferably, therefore, theprocess is conducted under such conditions that the hydrogenation isterminated after the calculated quantity of hydrogen hasbeen absorbed.If starting products of Formula IV are employed in which phenolichydroxy groups are protected by benzyl groups, these protective groupscan be removed during the course of hydrogenation.

Catalytic hydrogenation is particularly suitable for the production ofthose compounds of Formula I in which R represents H,I-I.

The reduction of the compounds of Formula IV is also successful withother reducing agents. Thus, it is possible to convert flavanones intothe flavanes of Formula I by means of diborane; for this purpose, thefiavanone is dissolved, for example, in diethylene glycol dimethylether; diborane is introduced under cooling; and the solution is allowedto standovemight at room temperature. Furthermore, flavanones can beconverted into their thioketals, preferably their ethylenethioketals,which are then split reductively, for the most part by reaction withRaney-metals.

Flavonols can selectively be converted to 3-hydroxyflavanones of theFormula I (R OH, R O), for example by means of sodium dithionite in anaqueous medium, or by means of Pd charcoal in tetralin, the tetralinserving simultaneously as solvent and as hydrogen donor. In the lastreaction, preferably temperatures around 200 C. are employed; normally,the reaction is finished after 1 to 5 hours.

It is further possible to carry out the reduction of a flavone in such amanner that simultaneously the keto group in the 4-position is reducedto a CHOH-or to a CH, group. For example, the 4-hydroxy-flavanederivative is obtained by reduction with sodium or aluminum amalgam orwith Raney-nickel in aqueous alcohol, it being possible to operate atroom temperature or up to boiling temperature; the reaction is finishedafter 1% hour to 3 days.

The starting compounds of Formula IV can be obtained in accordance withconventional methods. For example, the flavylium salts are obtainable bycondensation of a 2,5-dihydroxy-benzaldehyde which is, ifdesired,etherified or esterified in the -position, with a ketone of the formulaR CI-l COAr; the A or A flavenes are obtainable by reduction of thecorresponding flavylium salts with lithium aluminum hydride; theremaining compounds of Formula IV can be obtained according to themethods described in this application.

It is furthermore possible to introduce a double bond in the2,3-position of a compound of Formula I by treating with dehydrogenatingagents. Here, it is not necessary to isolate the compound I since it ispossible to make the dehydrogenating agent act upon the raw reactionmixture which contains the compound I. Further, in processes forproducing the compound I, a dehydrogenating agent can be added, andafter the reaction is finished, the 2,3-dehydro derivative of I can bedirectly isolated.

The expression dehydrogenating agents is to be understood, in accordancewith the invention, in a broad sense. Suitable agents are, for example,halogens, such as chlorine, bromine, or iodine, N-' haloamides, seleniumdioxide, hydrogen peroxide, dehydrogenation catalysts, such aspalladium; preferably in the presence of a hydrogen acceptor,halogenated quinones, such as chloranil and 2,3-dichloro-S,6-dicyanoquinone, pyridinium-bromideperbromide, and othersubstances which generate active halogen. The dehydrogenation may becarried out in one stage, or also in several stages, for example, byconverting a flavanone into the corresponding isonitroso-ketone andsubsequent hydrolysis or reduction of the same.

Flavones of the Formula I (R, 0, double bond in the 2,3-position) areespecially suitable as 2,3-dehydro derivatives. For producing suchflavone derivatives, the corresponding flavanones can be treated withdehydrogenating agents. It is also possible to produce the flavanonesonly in situ. For example, ketones of the above Formula H (R, O) can beemployed in the reaction in place of the flavanones (I, R, O). In thiscase, the fiavanones are produced as intermediates. As ketones ofFormula II (R, O), the chalcones (X CR CH) are particularly suitable.

It is further possible to operate in such a manner that the ketones (II,R, O) are also not produced in an isolated manner, but are produced insitu only. For example, a substituted 2-hydroxy-acetophenone can be madeto react with an aldehyde ArCHO, and the reaction mixture can be treatedwith one of the mentioned dehydrogenation agents.

For purposes of dehydrogenation, it is possible, for example, to treatthe flavanones (I, R, O) with halogens, preferably chlorine or bromine,and subsequently split off hydrogen halide. If the ketones (II, R, O)constitute the initial starting materials, the

chalcone dihalides are produced as intermediates which, under theinfluence of basic agents (preferably methanolic or ethanolic sodium orpotassium hydroxide) lose 2 mols of hydrogen halide and are converted toflavones under simultaneous cyclization. In this reaction, phenolic OHgroups can also be present in protected form and can be freed asdescribed above. If a flavanone is chosen as starting point, thereaction can be conducted through the 3-halo-flavanone stage. lt can beaccomplished completely. for example, by introducing a halogen atom inthe 3-position of a flavanone derivative which is unsubstituted in the3- position, this being done by bromination under the influence oflight. The dehydrohalogenation of the 3- halo-flavanones can be carriedout with alcoholic, preferably methanolic alkali or ethanolic potassiumhydroxide, or also by the effect of tertiary amines, such as collidine,lutidine, pyridine, picoline, further with lithium chloride or bromide,and lithium carbonate in dimethyl formamide, preferably at roomtemperature.

In place of halogens, N-halogeno-carboxylic acid amides or -imides canbe used, too, during the halogenation of the compounds (I or II, R, 0),preferably N-chloroor N-bromo-succinimide. In this case, the. reactiontakes place in stages, according to the quantity of the agent used. If aflavanone is the starting point, at first a halogen atoms is introducedin the 3-position. By means of excess reagent, the conversion to flavonetakes place, it being possible that a halogen atom is retained in the3-position. The reaction is preferably carried out by several hoursboiling of the reactants in an inert organic solvent, preferablychloroform or carbon tetrachloride. Peroxides, preferably benzoylperoxide and/or irradiation of the solution accelerate the reaction.

Another dehydrogenation method comprises the reaction of the ketone (II,R, O) or flavanone (I, R O) with selenium dioxide. The reaction ispreferably conducted at high temperatures, a high-boiling solvent beingemployed. Preferably, xylene, amyl alcohol, acetic anhydride, andsimilar agents are suitable; the reaction time is generally 3 to 15hours. If acetic anhydride is used, the intermediate protection ofphenolic hydroxy groups is unnecessary. In other cases, the reaction ismore successful with protected, for example, esterified hydroxy groups.

A further dehydrogenating agent which can be advantageously used ishydrogen peroxide in alkaline solution. If a chalcone is selected as thestarting product, the reaction takes place via the epoxide and the3-hydroxy-flavanone. 3-Hydroxy-flavones (flavonols) are particularlyadvantageously obtained by this method. Preferably, the reaction isallowed to take place in aqueous, aqueous-alcoholic, or alcoholic, forexample methanolic, solution, and at room temperature; at the beginningof the reaction, cooling is also employed. The peroxide is used inexcess in approximately a 10 to 30 percent proportion in aqueoussolution. The reaction is essentially finished after several hours;advantageously, the solution is allowed to stand for some time, forexample overnight, in order to end the reaction completely.

A further method is the dehydrogenation of flavanones (preferably of3-hydroxy-flavanones) with palladium in the presence of a hydrogenacceptor.

Generally, unsaturated acid derivatives, such as cinnamic acid, maleicacid anhydride, or similar compounds are used as-acceptors. Preferably,the process is carried outin the presence of an inert solvent, such aswater, and at about between 50 C. and the boiling point of the solventused.

A furthervariant consists in the reaction of the flavanones with estersof nitrous acid, preferably butyl nitrite or isoamyl nitrite, in thepresence of acid, preferably a mineral acid, and subsequentconversionsof the obtained isonitroso-ketones. For example, theisonitroso-ketone can be converted into the corresponding flavonol byhydrolysis with boiling percent sulfuric acid in glacial acetic acid orwith hydrochloric acid. If an excess of acid is employed during thenitroso group introduction into the flavanone,

, the flavonol is obtained directly. If, on the other hand,-

the isonitr'oso-ketone is treated with reducing agents, for examplestannous chloride, 3-amino-flavones are produced.

The above enumeration of the dehydrogenating agents which can beemployed in accordance with the invention is only exemplary. It is, ofcourse, possible within the scope of the invention to use also otherdehydrogenating agents under suitable conditions.

In a compound of Formula I, it is possible to convertone or several ofthe substituents R, to R into other substituents R to R Thus, protectedhydroxy and/or amino groups may be liberated by hydrolysis or reduction;For example, hydroxy groups and/or acylated amino groups which had beenesterified or protected in the form of tetrahydropyranyl ether or benzylether can be hydrolyzed in a basic, neutral, or acidic medium, preferredbases being aqueous, aqueous-alcoholic, or alcoholic sodium or potassiumhydroxide, the preferred acids being hydrochloric and sulfuric acids.Aside from simple hydrolysis, benzyloxy, benzylamino, or benzalaminogroups can be split hydrogenolytically.

It is furthermore possible to alkylate or to acylate' free hydroxygroups. Such hydroxy groups can be of the-phenolic type (in the 6-, 3-,and/or 4'-position) or of the alcoholic type (in the 3- or 4-position,or as a substituent attached to an alkoxy group).

The etherification can, for example, take place by. reaction withcorresponding alkyl halogenides, sulfates, or lower alkyl esters in thepresence of an al-' kali, such as sodium or potassium hydroxide orcarbonate; one of the customary inert solvents can also be present. Ofimportance is the conversion of phenolic hydroxy groups into such alkoxygroups which still contain basic or acidic groups as substituents.Correspondingly, the phenolic starting compounds can be' reacted, forexample, with methyl iodide, dimethyl sulfate, ethyl-, propyl-,isopropyl-, n-butyl-, isobutyl-, amyl', and isoamyl-halogenides, 2-dialkylamino-ethyL, such as 2-dimethylamino-ethyl-,2-diethylamino-ethyl-, 2-methylamino-ethyl-halogenides,2-pyrroiidino-ethyl-, 2-piperidino-ethyl-, 2-morpholinoethyl-, or3-dialkylamino-propyl-halogenides, or with the corresponding alcohols.Such etherifications are carried out, for example, according to theprinciple of a Williamsonsynthesis, the corresponding alkali phenolates(sodium or potassium phenolates) being made the starting materials.

the corresponding alcohols and/or the substituted amino alcohols in thepresence of acidic catalysts, such Moreover, it is possible to react thefree phenols with v as sulfuric acid, phosphoric acid,p-toluene-sulfonic acid. It is also possible to etherify the phenolicOH- groups with halogen carboxylic acids or their derivatives, forexample esters, amides, nitriles; particularly, the residue R -CO--CHR-O- can be introduced in this manner in the 6-position. Suitable halogencarboxylic acids are, for example, chloro-acetic acid or bromo-aceticacid, a-chloroor a-bromo-propionic acid, a-chloro-butyric ora-bromo-butyric acids, achloro-valeric or a-bromo-valeric acid,a-chlorocaproic or a-bromo-caproic acids, a-chloroor abromo-heptanoicacids, such as a-chloroor abromoisoamyl acetic acid, as well as theirmethyl and ethyl esters, amides, dialkylamides, or nitriles.

An acylation of hydroxy groups can be provided by heating same with ananhydride or halogenide of acetic, propionic, butyric, isobutyric,valeric, isovaleric, or caproic acid (e.g. acetyl chloride)advantageously in the presence of a base, such as pyridine or an alkalisalt of the corresponding acid, or also a small quantity of mineralacid, such as sulfuric acid or hydrochloric acid.

Amino groups can be alkylated, for example, by reacting with thecorresponding alkyl halogenides, such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl halogenides, or with dimethyl or diethylsulfate. Furthermore, amino groups can be acylated just like phenolichydroxy groups with acid halogenides or anhydrides in the presence ofbases, such as pyridine. A reduction of the obtained acyl amides, forexample with lithium aluminum hydride in ether or tetrahydrofuran, leadsto the corresponding monoalkylamines; keto groups in the 4-position,which can be present, can be reduced at the same time.

It is further possible to reduce nitro groups in the 6-, 3'-, and/or4'-position to amino groups by means of catalytically activated hydrogenor by way of other chemical reducing agents. Suitable as chemicalreducing agents are mainly metals, such as iron, zinc, tin, in thepresence of acids, such as hydrochloric, sulfuric, or acetic acid andalso with the preferable addition of an inert organic solvent. A ketogroup in the 4-position can be removed by reduction, or can be convertedto a hydroxy group. In addition to one-stage processes (catalytichydrogenation, for example 'with platinum oxide in glacial acetic acidor ethanol, reaction with aluminum amalgam or with complex hydrides,such as lithium aluminum hydride, in certain cases in the presence ofaluminum chloride, or sodium borohydride), it is also possible to usemulti-stage methods. Thus, it is possible to convert the keto group intoits thioketal, preferably its ethylene thioketal, which can then besplit reductively, preferably by reaction with Raney-metals.

It is also possible to convert a keto group in the 4- position into theoxime and to reduce the latter to the corresponding amine in a catalyticor chemical manner. Particularly suitable reducing agents are complexhydrides of the type of the lithium aluminum hydride, whereasRaney-nickel is especially suited as a hydrogenation catalyst. The aminethus obtained can be converted into the 4-hydroxy compound by treatingwith nitrous acid.

In a compound of Formula I in which R =R-,-CO -CHR,,--O, the residue Rcan be further converted into another residue R by esterification,saponification, amidation, or alkylation. An esterification is carriedout in the conventional manner in case of such compounds in which Rrepresents a hydroxy group. For example, the reaction can be carried outwith methanol, or ethanol, in the presence of acids, preferably in thepresence of an organic solvent and with the use of azeotropicesterification methods, or also by treating with diazomethane ordiazoethane in ether, tetrahydrofuran, or dioxane.

If the residue R represents methoxy or ethoxy, then it can be saponifiedin accordance with the abovedescribed methods, or it can be convertedinto the cor-- responding acid amides by reaction with ammonia orprimaryand/or secondary alkylamines, and in certain cases cyclic amines. If theresidue R represents a free amino group, it can be converted into analkylamino and/or dialkylamino group, which can, if desired, also becyclic, by reaction with the corresponding alkyl halogenides, such asmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, amyl, isoarnylhalogenides, or with dimethyl or diethyl sulfate, or with1,4-dichloro-or 1,4- dibromo-butane, 1,5-dichloroor l,5-dibromopentane.

Furthermore, it is possible to introduce a chlorine, bromine, or iodineatom in the 3-position, for exampleby treating a flavanoid of Formula I(R, O) which is unsubstituted in the 3-position, withhalogenatingagents, such as N-chloroor N-bromo-succinimide, or with freehalogen. Such halogenation processes are car-' ried out in the presenceof an inert solvent, such as chloroform, carbon tetrachloride, or otherhalogenated hydrocarbons. It is possible to operate in the cold, atambient temperature, or at higher temperatures. Thereaction can bepromoted by irradiation with elec-- tromagnetic waves of about thewavelength of light, or by adding suitable catalysts, such as benzoylperoxide. 3-I-Ialo-flavanones are also obtainable by treating 3-'hydroxy-flavanones with inorganic acid halogenides, such as thionylchloride, phosphorus trior pen-L tachloride, or bromide.

A hydroxy group in the 3-position can be introduced subsequently bytreating flavanones which are unsubstituted in the 3-position withhydrogen peroxide in the presence of ferrous sulfate or with leadtetraacetate in glacial acetic acid. In the latter case, the 3-acetateis produced from which the 3-hydroxy compound can later be obtained bysaponification with a mineral acid, for example hydrochloric or sulfuricacid.

The introduction of an amino group into the 3-position is accomplishedby reacting a flavanone which is unsubstituted in the 3-position with anester of nitrous acid so that an isonitroso-ketone is produced, and thenreducing the intermediate with, for example, stannous chloride inglacial acetic acid/hydrochloric acid, thereby obtaining3-amino-flavones.

An amino group in the 3-position can also be introduced by means of theNeber-reaction. In this case, the starting point is an oxime of aflavanone of Formula I (R H, R. O) which is converted into itsarylsulfonyl derivative, preferably by reaction with ptoluene sulfonylchloride in the presence of pyridine. The arylsulfonyl oxime isconverted into a 3-aminoflavanone under the influence of basiccatalysts, such as potassium alcoholate and by splitting off thearylsulfonyl group. The conversion is suitably carried out in thepresence of a suitable solvent, such as benzene, and at temperaturesbetween 0 C. and room temperature.

An alkyl group, preferably a methyl or ethyl group, can be subsequentlyintroduced into the 3-position by alkylation, preferably methylation orethylation of a flavane derivative of Formula I unsubstituted in the 3-position. This can be done, for example, by direct reaction of aflavanone with alkyl halogenides, such as methyl or ethyl halogenides,in the presence of a base, or by alkylation of the corresponding enaminewith subsequent hydrolysis. Additionally, a 3-methyl group can beintroduced into flavones of Formula I by heating the parent flavonecompound with paraformaldehyde in glacial acetic acid/hydrochloric acidand subsequent reduction of the produced chloro-methyl group with zincdust.

It is then possible to convert basic flavanoids of Formula I into theirphysiologically compatible acid addition salts by treating with acids.For this conversion, such acids are preferably used which yieldphysiologically compatible and pharmaceutically acceptable salts. Thus,organic and inorganic acids can be used, as for example aliphatic,alicyclic, araliphatic, aromatic, or heterocyclic monoor polybasiccarboxylic or sulfonic acids, such as formic acid, acetic acid,propionic acid, pivalic (trimethylacetic) acid, diethyl acetic acid,oxalic acid, malonic acid, succinic acid, pirnelic acid, fumaric(allomaleic) acid, maleic acid, lactic acid, tartaric(dihydroxy-succinic) acid, malic acid, aminocarboxylic acids, sulfamicacid, benzoic acid, salicylic acid, phenylpropionic acid, citric acid,gluconic acid, ascorbic acid, isonicotinic acid, methane-sulfonic acid,naphthalene-monoand disulfonic acids, sulfuric acid, nitric acid,hydrohalogenic acids, such as hydrochloric acid or hydrobromic acid, orphosphoric acids, such as orthophosphoric acid.

Finally, flavanoids of Formula I which contain basic groups can also beconverted into their physiologically compatible quaternary ammoniumcompounds by treating with alkylation agents, such as methyl iodide,dimethyl sulfate, or ethyl halogenides.

The preferred groups of compounds which can be obtained in accordancewith this invention are as follows:

l 0 mcoonmo Y R3 wherein:

R represents H or alkyl of one to five carbon atoms and R represents OH,alkoxy of one to six carbon atoms, NI-I alkylated amino of one to eightcarbon atoms, 2-hydroxyethylamino, pyrrolidino, piperidino, ormorpholino,

R to R have the previously indicated meanings, and an additional doublebond can be present in the 2,3-position, wherein, however, the residue RCOCHR possesses a total of at most 10 carbon atoms;

f RD s 10 iii wherein:

R represents OH, alkoxy of one to five carbon atoms, acyloxy of one tosix carbon atoms, or R COCHR -O--,

R represents OH, alkoxy of one to five carbon atoms, acyloxy of one tosix carbon atoms, benzyloxy, dialkylaminoalkoxy of four to seven carbonatoms, or dialkylamino of two to four carbon atoms,

R represents H,OH, alkyl, or alkoxy of one to three carbon atoms,

R represents H or CH O,

R and R together can also represent methylene dioxy,

R R and R have the previously indicated meanings,

and wherein an additional double bond may be present in the2,3-position;

wherein, however, in case R H and R O and no double bond is present inthe 2,3-position, R is CH O only if R; is not simultaneously OH or CH Oand R is not CH O; and wherein, further, if R, O and a double bond ispresent in the 2,3-position, R is H only if R and R are notsimultaneously both OH or both CH O and R is not H or OH; or if R, isnot simultaneously C H O, R is not C H O or CH O and R is not H; or if Rand R are not simultaneously OH and R is not CH O;

wherein:

R represents H,OH or H,H or H,NH and R R R and R have the previouslyindicated meanings;

wherein:

R represents alkyl of one to three carbon atoms, R R R and R have thepreviously indicated meaning, and an additional double bond can bepresent in the 2,3-position;

bon atoms, or tetrahydropyranyl-(2)-oxy,

R to R have the previously indicated meanings,

and an additional double bond can be present in the 2,3-position,

wherein, however, in case R H and R O, and no double bond is present inthe 2,3-position, R is CH O only if R is not simultaneously CH O and Ris not CH O or CH OCH O, or if R is not OH and R and R togetherrepresent methylene dioxy only if R is not simultaneously OH; and Rrepresents H only if R and R are not simultaneously both CH O; andwherein, furthermore, if R ='O and a double bond is present in the2,3-position, R is H only if R and R are not simultaneously both OH orboth CH O and R is not H or OH; or if R and R are not OH and R is not CHO;

wherein:

R is alkoxy of one to three carbon atoms, R R R and R have thepreviously. indicated meaningsfand an additional double bond can bepresent in the 2,3-position;

II R4 wherein:

R to R have the previously indicated meanings, and an additional doublebond may be present in the 2,3-po sition;

wherein, however, if R H and R O, and no double bond is present in the2,3-position, R is CH O only if R is neither CH nor NH; and wherein,furthermore, if R O and a double bond is present in the 2,3-position, Ris H only if R and R are not simultaneously both OH or CH O or C H O, orif R is not C H O and R is not CH O; and R is OH only if R and R are notsimultaneously both OH or CH O, or R is not OH and R is not CH O;

wherein R is H ,OH, CH O, Cl-l or C 11 R is H, acyl of one to six carbonatoms, alkyl of 1-5 carbon atoms, dialkylaminoalkyl of four to sevencarbon atoms, tetrahydropyranyl- 2), or the group R COCHR R is HO,alkoxy of one to five carbon atoms or dialkylaminoalkoxy of four toseven carbon atoms, and

R is H or R R is HO, CH O, C H O, NH or alkylated, if desired cyclic,amino with a total of one to eight carbon atoms.

Of all the compounds of the invention, the most advantageous are:

3,4-dimethoxy--acetoxy-flavane;4-amino-6-hydroxy-4'-methoxy-flavanehydrochloride;

4,4'-dihydroxy-6,3-dimethoxy-flavane;4,6-dihydroxy-4-isoamyloxy-flavane; 3-methyl-6-ethoxy-34'-dimethoxy-flavanone; 3-methyl-4,6-dihydroxy-4'-methoxy-flavane;3-methyl-6-hydroxy-4-methoxy-flavanone;3-methyl-6-ethoxy-4'-isoamyloxy-flavanone;3-methyl-6-hydroxy-4'-isoamyloxy-flavanone;

6,3 ,4'-trimethoxy flavonal;

3 ,4 '-methylenedioxy-flavanone-6-oxyacetic ethyl ester;

'4-methoxy-flavanone-6-oxyacetic acid ethyl ester;

6-acetoxy-4-methoxy-flavane;

3-methyl-6-hydroxy-3',4'-dimethoxy-flavanone;3-methyl-4-dimethylamino-6-oxyacetic acid ethyl ester;

3,4-dimethoxy-6-hydroxy-flavane;

6, 3 '-dimethoxy-4 -hydroxy-flavanone;

6hydroxy-4'-isoamyloxy-flavanone;

3-methyl-6-hydroxy-4-methoxy flavane; 6-hydroxy-4-methoxy-flavanone.

The following compounds are new and valuable intermediates:

4-oximino-6-hydroxy-4-methoxy-flavane;

p-methoxy-propiophenone; 2-hydroxy-5-ethoxy-propiophenone;3,4-methylenedioxy-propiophenone;w-methoxy-3,4-methylenedioxy-acetophenone; 6,4-dihydroxy-flavyliumchloride; 6-hydroxy-4'-methoxy-flavylium chloride;6,4-dimethoxy-flavylium chloride; 6-methoxy-4'-hydroxy-flavyliumchloride; 6,3-dimethoxy-4'-hydroxy-t1avylium chloride;6,3',4-trihydroxy-flavylium chloride;3-methyl-6-hydroxy-4'-methoxyflavylium chloride;6-hydroxy-3,4'-dimethoxy-t1avylium chloride;3-methyl-6-hydroxy-3,4-methylenedioxy-flavylium chloride;3-methoxy-6-hydroxy-3,4 -methylenedioxy-flavylium chloride.

The novel flavanoids and also the compounds not subject to the provisionfirst mentioned above can be employed by admixing them with thecustomary medicinal excipients. Carriers include such organic orinorganic materials which are suitable for parenteral, enteral, ortopical application and which do not react with the novel compounds,such as, for example, water, vegetable oils, polyethyleneglycols,gelatins, lactose, amylose, magnesium stearate, talcum, vaseline, etc.

acid

Solutions, preferably oily or aqueous solutions, as well as suspensions,emulsions, or implants serve particularly well for parenteralapplication. Furthermore, for enteral application, tablets or drageescan be used; and for topical application, there can be employed salvesor creams which can, if desired, be sterilized or mixed with auxiliarysubstances, such as preservatives, stabilizers, wetting agents, orbuffers, or salts which influence the osmotic pressure.

The products of the invention are preferably employed in unit dosageform containing about 1 to 500 mg. of active ingredient.

BLOOD CHOLESTEROL LOWERING EFFECT OF FLAVANOlDS The blood cholesterollowering effect of the flavanoids was determined according to the methodof Counsell et al. (J. med. pharm. Chem. 5, 720, 1224' Normally fed ratswere treated with 25 mg/kg per os daily of the test substance for aperiod of 10 days. Thereafter, the animals were sacrificed, the serumcholesterol was determined colorimetrically and compared to that ofcontrol animals.

The following (average) results were obtained:

TABLE Cholesterol (mg/ ml. Serum) Found Decrease compared to controlEXPERIMENT 1 3,4'-Dimethoxy-6-acetoxyflavane 19.9 45.04-Amino-6-hydroxy-4'-methoxyflavane-hydrochloride 42.1 22.84,4'-Dihydroxy-6,3'-dimethoxy-flavane 42.2 22.74,6-Dihydroxy-4'-isoamyloxyflavane 44.4 20.5 3-Methyl-6-ethoxy-3,4'-

dimethoxy-flavanone 47.6 17.3 3-Methyl-4,6-dihydroxy-4'- methoxy-flavane48.0 16.9 Control 64.9

EXPERIMENT 2 3-Methyl-6-hydroxy-4'- methoxy-flavanone 35.3 33.93-Methyl-6-ethoxy-4'- isoamyloxy-flavanone 39.5 29.7

3-Methyl-6-hydroxy-4'- s isoamyloxy-flavanone 49.3 19.96-Hydroxy-3',4-methylenedioxy-flavanone 5 L0 18.26,3',4-trimethoxyflavonol 51.0 18.2Ethyl-3',4'-methylenedioxy-flavanone-6-oxyacetate 5 2.7 16.5 Control69.2

EXPERlMENT 3 Ethyl-4'-methoxy-flavanone- 6-oxyacetate 42.8 16.7 Control67.5

Thus it is shown that the flavanoids according to the invention have asubstantial blood cholesterol lowering effect.

Aside from the pharmacological utility of the compounds of thisinvention, they all can be used as intermediates to make even moresophisticated final products by substituting different moieties onto thethree rings of the flavane system. Such reactions can be conducted inaccordance with the teachings herein as well as in the prior art.

Without further elaboration it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The following preferred specific embodiments are,therefore, to be construed as merely illustrative, and not lirnitativeof the remainder of the specification and claims in any way whatsoever.

EXAMPLE 1 1 g. Z-hydroxy-S-methoxy-acetophenone and 1.15 g.p-isoamyloxy-benzaldehyde are dissolved in 8 ml. ethanol, mixed with 5g. of 50 percent solution of sodium hydroxide (or potassium hydroxide),and agitated for 5 minutes, the mixture coagulating to a reddish,semi-solid mass. The mixture is then mixed with water; the precipitateis removed by suction, and a recrystallization from ethanol isconducted. The obtained 6- methoxy-4'-isoamyloxy-flavanone melts at ll5-l 16.

In an analogous manner, the following compounds are obtained by reactingwith the correspondingly substituted benzaldehydes:

From 2-hydroxy-5-methoxy-acetophenone:

6 methoxy-4'-isobutoxy-flavanone, m.p. 109-1 10 6-methoxy-4-(Z-dimethylaminoethoxy)-flavanone,

6-methoxy-4 3 -dimethylaminopropoxy flavanone, m.p. 91

6-methoxy-4'-hydroxy-flava.none, m.p. 1781 796-methoxy-4-benzyloxyflavanone, m.p. l46147 From2-hydroxy-5-methoxy-propiophenone (obtained by rearrangement ofhydroquinonedipropionate in an aluminum chloride sodium chloride meltand subsequent partial methylation with dimethylsulfate):

3-methyl-6-methoxy-4-isoamyloxy-flavanone3-methyl-6-methoxy-4'-isopropoxy-flavanone3-methyl-6-methoxy-4-isobutoxy-flavanone3-methyl-6-methoxy-4-(2-dimethylaminoethoxy)- flavanone3-methyl-6-methoxy-4-(S-dimethylamino-propox- 3 -methyl-6,3'-dimethoxy-4 -isoamyloxy-flavanone 3-methyl-6,3 -dimethoxy-4'-isobutoxy-flavanone 3-methyl-6,3 -dimethoxy-4 -isopropoxy-flavanone3-methyl-6,3-dimethoxy-4'-( 2- dimethylaminoethoxy)-flavanone3-methyl-6,3-dimethoxy-4'-(3- dimethylaminopropoxy)-flavanone3-methyl-6-methoxy-3 ',4 '-propylenedioxy-flavanone 3-methyl-6-methoxy-3 ,4 '-ethylenedioxy-flavanone 3-methyl-6-methoxy-3,4-methylenedioxyflavanone From 2,5-dihydroxy-acetophenone:

6-hydroxy-4-dimethylamino-flavanone (hydrochloride, m.p. l86188 withdecomposition) 6 From 2,5-dihydroxy-a-methoxy-acetophenone (obtained bytreating .hydroquinone-bis-methoxyacetate with aluminum chloride/sodiumchloride);

3-methoxy-6-hydroxy-4'-isopropoxy-flavanone3-methoxy-6-hydroxy-4-isobutoxy-flavanone3-methoxy-6-hydroxy-4-isoa.myloxy-flavanone3-methoxy-6-hydroxy-4-(2-dimethylaminoethoxy)- flavanone 203-methoxy-6-hydroxy-4'-(2-dimethylaminopropoxy)-flavanone3-methoxy-6-hydroxy-3 ',4 -methylenedioxyflavanone 3-methoxy-6-hydroxy-3,4 '-ethylenedioxy-flavanone 3-methoxy-6-hydroxy-3 ',4'-propylenedioxyflavanone3,3'-dimethoxy-6-hydroxy-4-isopropoxy-flavanone3,3'-dimethoxy-6-hydroxy-4'-isobutoxy-flavanone 3,3'-dimethoxy6-hydroxy-4'-isoamyloxy-flavanone 3 ,3 '-dimethoxy-6-hydroxy-4 2-dimethylaminoethoxy)-flavanonc 3 ,3 -dimethoxy-6-hydroxy-4-( 3-dimethylaminopropoxy)-flavanone 3,3',4-trimethoxy-6-hydroxy-flavanoneFrom 2,5-dihydroxy-a-eth0xy-acetophenone:3-ethoxy-6-hydroxy-4'-isoamyloxy-fiavanone From the corresponding2-hydroxy-5-alkoxyacetophenones (obtained by boiling for 2 hoursequimolar quantities of 2,S-dihydroxy-acetophenone, alkyl bromide, andaqueous sodium hydroxide in ethanol):

' 6-isoamyloxy-4'-methoxy-flavanone, m.p. 909 16-ethoxy-4-methoxy-flavanone 6-is0propoxy-4-methoxy-flavanone6-isobutoxy-4'-methoxy-flavanone6-(2-dimethylaminoethoxy)-4'-methoxy-flavanone 6-(B-dimethylaminopropoxy )-4 '-methoxy-flavanone6,4'-diisoamyloxy-fiavanone 6,4-diisopropoxy-flavanone6,4'-diisobutoxy-flavanone 6,4'-bis-(Z-dimethylaminoethoxy)-flavanone 6,4 '-bis-( B-dimethylaminopropoxy )-flavanone6-isopropoxy-4-isobutoxyflavanone 6-isopropoxy-4'-isoarnyloxy-flavanone6-isopropoxy-4'-(2-dimethylaminoethoxy) flavanone6-isopropoxy-4'-(3-dimethylaminopropoxy)- flavanone6-isobutoxy-4'-isopropoxy-flavanone 6-isobutoxy-4-isoamyloxy-flavanone6-isobutoxy-4'-(2-dimethylaminoethoxy)-flavanone6-isobutoxy-4'-(3-dimethylaminopropoxy)- flavanone6-isoamyloxy-4'-isopropoxy-flavanone 6-isoamyloxy-4'-isobutoxy-flavanone6-isoamyloxy-4'-(2-dimethylaminoethoxy)- flavanone6-isoamyloxy-4-(3-dimethylaminopropoxy)- flavanone6-(2-dimethylaminoethoxy)-4-isopropoxyflavanone6-(2-dimethylaminoethoxy)-4-isobutoxy-flavanone6-(2-dimethylaminoethoxy)-4'-isoamyloxyflavanone-6-(2-dimethylaminoethoxy)-4-(3- dimethylaminopropoxy)-flavanone6-(3-dimethylarninopropoxy)-4-isopropoxyflavanone6-(S-dimethylaminopropoxy)-4'-isobutoxyflavanone6-(3-dimethylaminopropoxy)-4'-isoamyloxyflavanone6-(3-dimethylaminopropoxy)-4-(2- dimethylaminoethoxy)-flavanone6-isoamyloxy-3 ,4 '-dimethoxy-flavanone 6-etl1oxy-3,4-dimethoxy-flavanone EXAMPLE 3.

l g. 2'-hydroxy-5-methoxy-4-isopropoxy chalcone, obtained bycondensation of 2-hydroxy-5-methoxy-- 20 acetophenone withp-isopropoxy-benzaldehyde as in- Example 1, but isolated after havingbeen allowed to stand overnight at room temperature, is dissolved in 20ml. 2n sodium hydroxide, cooled to mixed with 1 ml. 30 percent hydrogenperoxide, and allowed to stand for hours at 0. After another addition ofI ml percent hydrogen peroxide and further 24 hours standing at 0, thesolution is acidified with acetic acid (pH 4), the precipitate isremoved by suction, well washed with ether, and the residue whichconsists of 3- 30 hydr'oxy-6-methoxy-4'-isopropoxy-flavanone isrecrystallized out of methanol.

According to the same 'method, the following compounds are produced fromthe corresponding 5'- methoxy-chalcones:

3-hydroxy-6-methoxy-4'-isobutoxy-flavanone3-hydroxy-6-methoxy-4-isoamyloxy-flavanone 3 -hydroxy-6-methoxy-42-dimethylaminoethoxy flavanone 3 -hydroxy-6-methoxy-4 3-dimethylaminopropox- 3-hydroxy-6,3 '-dimethoxy-4 -isopropoxy-flavanone3-hydroxy-6,3',4'-trimethoxy-flavanone I 3-hydroxy-6,3 '-dimethoxy-4'-ethoxy-flavanone 3-hydroxy-6,3"-dimethoxy-4'-isobutoxy-flavanone3-hydroxy-6,3 -dimethoxy-4 -isoamyloxy-'flavanone 3-hydroxy-6,3'-dimethoxy-4 2- dimethylaminoethoxy)-flavanone3-hydroxy-6,3-dimethoxy-4'-( 3- dimethylaminopropoxy)-flavanone 3-hydroxy- 6methoxy-3 ,4 '-methylenedioxyflavanone 3-hydroxy-6-methoxy-3,4 -ethylenedioxy-flavanone 3 -hydroxy-6-methoxy-3 ,4 '-propylenedioxy-I flavanone From the corresponding 2',5'-dihydroxy-chalcones or5-tetrahydropyranyl-(2)-oxy-chalcones, the corresponding3,6-dihydroxy-flavanones, substituted in the 4'- or the 3',4'-position,are obtained.

EXAMPLE 4.

2 g. 2-hydroxy-5-methoxy-acetophenone and 1.8 g.3-methoxy-4-hydroxy-benza1dehyde are dissolved in 38 m1. ethanol andmixed, dropwise, with a solution of 20 65 g. potassium hydroxide in 14ml. water. After briefly heating to 4050, the mixture is kept standingfor 2 days under nitrogen, then stirred into water, acidified withdilute hydrochloric acid, and extracted with chloroform. The solvent isdistilled off in vacuum; the residue is dissolved in 13 ml ethanol, ismixed with 3.3 ml. water and 1.3 g. sodium acetate and heated for 2hours on a steam bath. Then, it is stirred into water, extracted byether, and the extract is washed with water and dried over sodiumsulfate. After the ether is removed, the residue is recrystallized outof methanol. The obtained 6,3'-dimethoxy-4'-hydroxy-flavanone melts atl49150.

In an analogous manner, the following compounds are produced:

6,3 -dimethoxy-4'-ethoxy-flavanone, m.p. 154

6-hydroxy-3 '-methoxy-4 '-ethoxy-flavanone, m.p.

6-methoxy-3 ,4 '-methylenedioxy-flavanone, m p.

6,4'-dihydroxy-3 '-methoxy-flavanone, m.p. 2 l 2-21 6-hydroxy-3 ,4'-ethylenedioxy-flavanone 6-hydroxy-3 ,4-propylenedioxy-flavanone6-methoxy-3 ,4 '-propylenedioxy-flavanone 6-methoxy-3 ,4'-ethylenedioxy-flavanone 6,3 -dimethoxy-4 -isopropoxy-flavanone 6,3'-dimethoxy-4'-isobutoxy-flavanone 6,3 '-dimethoxy-4-isoamyloxy-flavanone 6,3 '-dimethoxy-4'-( Z-dimethylarninoethoxyflavanone 6,3 '-dimethoxy-4-( gqdimethylaminopropoxyy flavanone6-hydroxy-3'-methoxy-4'-isopropoxy-flavanone 6-hydroxy-3 '-methoxy-4'-isobutoxy-flavanone 6-hydroxy-3 '-methoxy-4 -isoamyloxy-flavanone6-hydroxy-3'-methoxy-4-(2-dimethylaminoethoxy)- flavanone 6-hydroxy-3'-methoxy-4 3 -dimethylaminopropoxy)-flavanone EXAMPLE 5.

A hot ethanolic solution of 2.6 g. 2-hydroxy-5- acetamido-acetophenoneand 2.4 g. p-isopropoxybenzaldehyde is mixed with 8 ml. piperidine andallowed to stand for 6 days at 25. Then, the mixture is stirred intowater, the 6-acetamido-4 -isopropoxyflavanone obtained thereby removedby suction, washed with water, and recrystallized out of ethanol.

In an analogous manner, the following compounds are produced:

6-acetamido-4'-isobutoxy-flavanone 6-acetamido-4'-isoamyloxy-flavanone6-acetamido-4'-(2-dimethylaminoethoxy)-flavan0ne 6-acetamido-43-dimethylaminopropoxy.)-

flavanone 6-acetamido-3 '-methoxy-4-isopropoxy-fiavanone 6-acetamido-3'-methoxy-4 -isoamyloxy-flavanone6-acetamido-3-rnethoxy-4'-(2-dimethylaminoethoxy)-flavanone6-acetamido-3 ,4 -ethylenedioxy-flavanone 6-acetamido-3 ,4-propylenedioxy-flavanone By 8 hours boiling of these compounds with 10percent methanolic hydrochloric acid, the hydrochlorides of thecorresponding 6-amino compounds are produced.

The starting substance, 2-hydroxy-5- acetamidoacetophenone, can beobtained from phydroxy-acetanilide In the above-described reactions ofthe compounds of Formulas II and III, the phenolic hydroxy groups can bepresent in protected (blocked) form; the blocking groups can be splitoff under the conditions of condensation. Thus, it is possible tocyclize such compounds in which which is converted, by boiling withacetyl chloride in benzene in the presence of pyridine, into theacetate, and is subsequently rearranged by three hours heating withaluminum chloride at l40l 60.

If, as starting materials, 2-hydroxy-5- nitroacetophenone and3-nitro-4-isopropoxy-benzaldehyde (produced by alkylation of3-nitro-4-hydroxybenzaldehyde) are used, the6,3'-dinitro-4'-isopropoxy-flavanone is obtained.

In an analogous manner, the following compounds are obtainable.

6,3 '-dinitro-4-ethoxy-flavanone 6,3-dinitro-4-isobutoxy-flavanone6,3-dinitro-4'-isoamyloxy-flavanone6,3-dinitro-4'-(2-dimethylaminoethoxy)-flavanone6,3-dinitro-4'-(3-dimethylaminopropoxy)- flavanone If2,S-dihydroxy-butyrophenone (obtained from hydroquinone-dibutyrate bymelting with aluminum chloride/sodium chloride) is used as startingsubstance, the following compounds can be obtained:

3-ethyl-6,4-dihydroxy-flavanone 3-ethyl-6-hydroxy-4-methoxy-flavanone3-ethyl-6-hydroxy-4-ethoxy-flavanone3-ethyl-6-hydroxy-4-isopropoxy-flavanone3-ethyl-6-hydroxy-4-isobutoxy-flavanone3-ethyl-6-hydroxy-4'-isoamyloxy-flavanone 3-ethyl-6-hydroxy-3 ,4-dimethoxy-flavanone 3-ethyl-6-hydroxy-3 '-methoxy-4 '-ethoxy-flavanone3-ethyl-6-hydroxy-3'-methoxy-4-isopropoxyflavanone3-ethyl-6-hydroxy-3-methoxy-4'-isobutoxyflavanone3-ethyl-6-hydroxy-3'-methoxy-4-isoamyloxyflavanone 3-ethyl-6-hydroxy-3'-methoxy-4 2- dimethylaminoethoxy)-flavanone 3 -ethyl-6-hydroxy-3'-methoxy-4 3- dimethylaminopropoxy)-flavanone 3-ethyl-6-hydroxy-3 ,4-methylenedioxy-fiavanone 3-ethyl-6-hydroxy-3 ,4-ethylenedioxy-flavanone 3 -ethyl-6-hydroxy-3 ,4-propylenedioxy-flavanone When using 2-hydroxy-S-methoxy-butyrophenone,the corresponding 6-methoxy-flavanones are obtained.

EXAMPLE 6.

EXAMPLE 7.

2 g. 1-p-anisyl-3-( 2 '-hydroxy5 -methoxyphenyl propanol are heated tothe boiling point in 10 ml. 2 percent methanolic hydrochloric acid for 4hours. Sub-- sequently the reaction mixture is concentrated under(obtained from 3-nitroanisal- 26 decreased pressure,6,4'-dimethoxy-flavane being crystallized, melting point 9 l 92.

In an analogous manner, 6-n-amyloxy-4'-methoxyflavane can be obtained.

EXAMPLE 8.

evaporated to form a dry substance, 6,4'-dihydroxy flavane beingobtained.

EXAMPLE 9.

2 g. l -p-anisyl-3-( 2 '-hydroxy-5 '-methoxyphenyl propylchloride aredissolved in the cold state in 200 ml of a 5 percent solution of sodiumhydroxide and is subsequently heated on a steam bath, therebycrystallizing out 6,4'-dimethyl-flavone. M.p. 9 l92.

EXAMPLE l0.

1 g 2'-hydroxy-5-methoxy-4-isoamyloxy-chalcone (m.p. 88; obtained from2-hydroxy-5-methoxyacetophenone and p-isoamyl-oxybenzaldehyde) is boiledfor 5 hours with 1 g selenium dioxide in 30 ml of isoamyl alcohol. Theprecipitated selenium is filtered off and washed with hot ethanol. Aftersteam distillation of the filtrate, the temperature is lowered, theprecipitate is removed by suction, dried, and extracted with chloroform.After the chloroform is distilled off, the obtained6-methoxy-4'-isoamyloxy-flavone is recrystallized out of ethanol; m.p.l59-l 60.

In an analogous manner, the following compounds are obtained:

6-meth0xy-4'-isopropoxy-flavone, m.p. l08l096-methoxy-4'-n-propoxy-flavone 6-methoxy-4'-n-butoxy-flavone6-methoxy-4'-sec. butoxy-flavone 6-methoxy-4-isobutoxy-flavone6-methoxy-4'-n-amyloxy-flavone 6-methoxy-4-n-hexyloxy-flavone6-methoxy-4-isohexyloxy-flavone 6-methoxy-4-heptyloxy-flavone6-methoxy-4-octyloxy-flavone 6-methoxy-4-nonyloxy-flavone6-methoxy-4-decyloxy-flavone 6-methoxy-4-benzyloxy-flavone, m.p. l62l 636-methoxy-4-(Z-dimethylaminoethoxy)-flavone 6-methoxy-4-(S-dimethylaminopropoxy)-flavone,

m.p. 109110 6,3-dimethoxy-4-benzyloxy-flavone 6,4'-dinitro-flavoneEXAMPLEI l.

l g. 2'-hydroxy-5-methoxy-4-isoarnyloxy-chalcone is dissolved in 40 mlethanol. After the addition of 40 ml. 5 percent solution of sodiumhydroxide, the mixture is cooled to 0; then, 10 ml. 16.5 percenthydrogen peroxide is added and kept at 0 for 2 hours. After having beenallowed to stand at room temperature for 18 hours, the reaction mixtureis mixed with a mixture of dilute hydrochloric acid and ice, theprecipitated 6- meth0xy-4-isoamyloxy-flavonol filtered off, washed withwater, and recrystallized out of ethyl acetate. M.p. l44l45.

In an analogous manner, the following compounds are produced from thecorresponding -methoxy-chalcones:

6-methoxy-4-n-propoxy-flavonol 6-methoxy-4-isopropoxy-flavonol6-methoxy-4'-n-butoxy-flavonol 6-methoxy-4'-sec. butoxy-flavonol6-methoxy-4-isobutoxy-flavonol 6-me thoxy-4'-n-amyloxy-flavonol6-methoxy-4-n-hexyloxy-flavonol 6-methoxy-4'-isohexyloxy-flavonol6-methoxy-4'-heptyloxy-flavonol 6-methoxy-4'-octyloxy-flavonol6-methoxy-4-nonyloxy-flavonol 6-methoxy-4'-decyloxy-flavonol6-methoxy-4'-benzyloxy-flavonol, m.p. l90l 9 1 From thetetrahydropyranyl ethers of the corresponding 5-hydroxy-chalcones, thefollowing compounds are obtained:

6-hydroxy-4-n-propoxy-fiavonol 6-hydroxy-4'-isopropoxy-flavonol6-hydroxy-4'-sec. butoxy-flavonol 6-hydroxy-4'isobutoxy-flavonol6-hydroxy-4'-n-amyloxy-flavono1 6-hydroxy-4-isoamyloxy-flavonol6-hydroxy-4'-n-hexyloxy-flavonol 6-hydroxy-4'-isohexyloxy-flavonol6-hydroxy-4'-heptyloxy-flavonol 6-hydroxy-4'-octyloxy-flavonol6-hydroxy-4-nonyloxy-flavonol 6-hydroxy-4-decyloxy-flavonol 6-hydroxy4-benzyloxy-flavonol EXAMPLE l2.

3 g, 2-hydroxy.-5-methoxy-propiophenone are boiled for 16 hours in 150ml. of absolute acetone with 4.5 g, p-isopropoxy benzoic acid chlorideand g,anhydrous potassium carbonate. The acetone is distilled off invacuum; the residue is mixed with water and shaken out by ether. Afterdrying, the ether is eliminated, and the residue is dissolved in 15 ml.dry pyridine at 50 and mixed, under stirring, with 1.4 g. groundpotassium hydroxide. After 30 minutes, the reaction mixture is acidifiedwith 10 percent acetic acid, the separated oil phase is extracted withchloroform and dried over sodi- 3-methyl-6-hydroxy-4-isoamyloxy-flavoneStarting from 2-hydroxy-a.5-dimethoxyacetophenone, the followingcompounds are obtained:

3,6-dimethoxy-4'-ethoxy-flavone 3 ,6-dimethoxy-4 '-isopropoxy-flavone 3,6-dimethoxy-4 -isobutoxy-flavone 3,6-dimethoxy-4'-isoamyloxy-flavone 3,6-dimethoxy-4 '-benzyloxy-flavone EXAMPLE 13.

From 2-hydroxy-5-methoxy-acetophenone and pbenzyloxybenzoyl-chloride,6-methoxy-4-benzyloxyflavone is produced, analogously to Example 12,melting point: l62-l 63.

1.5 g, 6-methoxy-4'-benzyloxy-flavone are suspended in 50 ml. glacialacetic acid and 50 ml. concentrated hydrochloric acid and heated on thesteam bath for 1 hour. The solvent is distilled off in vacuum and thecrude 6-methoxy-4-hydroxy-flavone is mixed with water, filtered off,washed, and, in the moist state, recrystallized from ethanol, m.p. 226.

Into 25 ml, absolute acetone 2.7 g, 6-methoxy-4'- hydroxy-flavone,2.6.g', l-chloro-3- dimethylaminopropane, and 5.6 g. anhydrous potassiumcarbonate are added and boiled, with stirring, for 24 hours. The mixtureis filtered in the hot state, the filtrate is concentrated by boiling,and the residue is mixed with water. The crude 6-methoxy-4'-(3dimethylarninopropoxy)-flavone is removed by suction and recrystallizedout of ethanol; m.p. 109l 10.

In an analogous manner, the following compounds are produced:

6-methoxy-4 2-dimethylaminoethoxy )-flavone 3 ,6-dimethoxy-4Z-dimethylaminoethoxy )-fl avone 3 ,6-dimethoxy-4 3-dimethylaminopropoxyAnalogously, 6,3 '-dimethoxy-4-benzyloxy-fiavone is converted to6,3'-dimethoxy-4-hydroxy-flavone and the latter to6,3'-dimethoxy-4'-(3-dimethylaminopropoxy)-fiavone.

EXAMPLE 14.

A hot, alcoholic solution of 3 g, 4-isopropoxy-2'-acetoxy-S-methoxy-chalcone-dibromide (obtained by bromination of the4-isopropoxy-2'-acetoxy5'- methoxychalcone in absolute chloroform) ismixed, under stirring, with 0.1 n solution of sodium hydroxide. After afew minutes, the mixture is cooled, the precipitate is filtered off andrecrystallized out of ethanol. The obtained6-methoxy-4-isopropoxyflavone melts at 108109.

EXAMPLE l5.

1 g, 2-hydroxy-5-isobutoxy-w-methoxyacetophenone (obtained fromhydroquinone-monoisobutyl ether and methoxyacetonitrile in ether underthe effect of zinc chloride/hydrogen), 1.8 g, p-methoxy-benzoic acidanhydride and 0.85 g, potassium-pmethoxybenzoate are finely groundtogether and heated for 3 hours under a pressure of 13 mm, Hg to 180.The reaction mixture is comminuted after cooling andboiled for 15minutes with 30 ml. of 8 percent aqueous ethanolic potassium hydroxidesolution. The ethanol is removed in vacuum, ml. water are added, and theseparated precipitate is filtered off.

.Recrystallization out of ethanol results, in 3,4-

dimethoxy-6-isobutoxy-flavone.

Analogously, other 6,3,4' and 3,6,4-trialkoxy and 6,4-dialkoxy-fiavonesare obtainable.

EXAMPLE 16.

4 g. hydroquinone, 8 g. p-methoxycinnamylbromide, and 5 g. freshlymolten zinc chloride are boiled for 6 hours in 35 ml, absolute benzene.Then, the mixture is cooled off, the organic phase is washed with water,

dried over sodium sulfate, and the solvent is removed,

under reduced pressure. The crude product is chromatographed at g.aluminum oxide, 6-hydroxy-4'- methoxy-flavone being obtained thereby.

Analogously, if hydroquinone-mono-tert. butyl ether is used in place ofhydroquinone, 6-tert. butoxy-4- methoxy-flavane is obtained.

EXAMPLE 1?.

3 g. 3-p-anisyl-3-p-anisyloxy-propylchloride and 0.3 g. tintetrachloride are heated in the bomb (carius tube) for 6 hours to 200.After cooling, the mixture is worked up with ether and aqueoushydrochloric acid; the ether phase is washed with a sodasolution;.drying is carried out over sodium sulfate; the solvent isdistilled off; and the crude product is recrystallized from methanol,6,4-dimethoxy-flavane of a melting point of 9l-92 being obtained.

EXAMPLE 1s.

3 g. 3-p-anisyl-3-p-anisyloxy-propanol are heated with 0.3 g, zincchloride in the bomb tube'for minutes to 200 and, after cooling, themixture is worked up as in the previous example,6,4-dimethoxyflavanebeing obtained; mp. 91 92.

EXAMPLE 19.

2 g. hydroquinone-mono-isopropyl ether and 2.1 g. p-methoxy-benzoylacetic acid ethyl ester (obtained by the effect of sodium upon a mixtureof p-methoxybenzoic acid ethyl ester and acetic acid ethyl ester) aremixed, in portions, with 3 g. phosphorus pentoxide and subsequentlyheated on the steam bath for 2 hours. Then the mixture is cooled, againthe same quantity of p-methoxybenzoyl acetic acid ethyl ester andphosphorus pentoxide is added, and another 2 hours heating is carriedout. The reaction product is mixed with water; the phosphoric acid isalmost neutralized with a solution of sodium hydroxide, the mixture issaturated with sodium chloride and extracted with chloroform. Theextract is washed with a sodium bicarbonate solution, is dried oversodium sulfate, and is evaporated to dryness. The 6-isopropoxy-4'-methoxyflavone remaining is recrystallized out ofethanol.

In an analogous manner, the following compounds are obtainable:

6-ethoxy-4'-isopropoxy-flavone 6-ethoxy-4'-isobutoxy-flavone6-ethoxy-4-isoamyloxy-flavone 6-isopropoxy-4-ethoxy-flavone6-isopropoxy-4-isobutoxy-fiavone 6-isopropoxy-4-isoamyloxy-flavoneEXAMPLE 20.

' 2 g, 6-hydroxy-4'-methoxy-flavy1ium chloride are stirredfor 30 minutesat room temperature in 100 ml.

absolute ether with 1.6 g, lithium aluminum hydride.

There is obtained 6-hydroxy-4-methoxy-2-flavene,

having a melting point of 183 (from methanol/ether).

In an analogous manner, there is produced: 6,4-

dimethoxy-2-flavene, m.p. 148l 50 EXAMPLE 21 1 g, platinum dioxide ispre-hydrogenated in 150 ml. methanol and is then mixed with 4 g,6,4'-dimethoxyflavylium-chloride. The hydrogenation is further continueduntil 2 mols of hydrogen have been absorbed; then, the mixture isfiltered, the methanol is distilled off, and the produced6,4-dimethoxy-flavane is recrystallized from methanol after beingpurified by activated carbon, m.p. 9 l 92.

Analogously, the following compounds are obtainable:

6-hydroxy-4-methoxy-flavane 6-methoxy-4-hydroxy-flavane 4 '-hydroxy-6,3'-dimethoxy-flavane 6,3,4-trihydroxy-flavane, as well as6-hydroxy-3,4'-dimethoxy-flavane From3-methyl-6-hydroxy-4-benzyloxy-flavyliumchloride, analogously the3-methyl-6,4'-dihydroxyflavane is obtained which is converted withacetic anhydride/pyridine into 3-methyl-6,4'-diacetoxy-flavane, m.p.165166 (from methanol).

EXAMPLE 22.

3.1 g, 6-methoxy-4'-isopropoxy-flavone are hydrogenated in ml. ethanolwith 5 g, Raney-nickel as the catalyst for 12 hours at The catalyst isfiltered of, the solvent is distilled off, and the residue ischromatographed through neutral aluminum oxide. The elution withchloroform results in 6-methoxy-4'- isopropoxy-flavanone and4-hydroxy-6-methoxy-4'- isopropoxy flavane, in addition to unchangedstarting substance.

EXAMPLE 23 1.1 g 6-hydroxy-4and 0.4 g, 5 percent palladium charcoal areheated in 40 ml. tetralin for 2 hours to 200. Then the mixture iscooled, the catalyst is filtered off, the extract is washed three timeswith a little ether and is acidified. During this process, 6-hydroxy-4'-isoamyloxy-flavanone is precipitated and is recrystallized out ofaqueous ethanol, m.p. 163-165.

EXAMPLE 24.

l .1 g, 3,6-dihydroxy-3 -methoxy-4-isopropoxyflavone and 8.5 g. sodiumcarbonate are introduced into ml. boiling water under nitrogen. Understirring, 20 g, sodium dithionite are added. After 30 minutes, themixture is cooled to 0, and after adding 15 ml. concentratedhydrochloric acid, the mixture is allowed to stand for 3 hours at 0. Theseparated, unchanged flavonol is filtered off, the filtrate isthoroughly extracted with ethyl acetate, the extract is dried oversodium sulfate, is concentrated to a dry product, and the obtained3,6-dihydroxy- 3'-methoxy- 4-isopropoxy-fiavanone is recrystallized outof aqueous ethanol.

In an anlogous manner, other 3,6-dihydroxyflavanones are obtainable.

The organic phase is separated, washed, and dried, and

EXAMPLE 25. room temperature, and then, after adding ml.

chloroform, it is allowed to stand overnight. The reaction mixture ispoured into 200'ml. chloroform, is washed with water and sodium chloridesolution and is dried over sodium sulfate. The residue obtained afterthe chloroform is removed, is dissolved in 300 ml. absolute ethanol andis boiled for 10 hours with active Raney-nickel. After the catalyst isfiltered off, the solution is concentrated. During this process, the 6-methoxy-4'-isoamyloxy-flavane is precipitated. It is recrystallized outof methanol.

In an analogous manner, the following compounds are obtained: 56-methoxy-4'-isopropoxy-flavane 2 g. 6,3'-dimethoxy-4'-hydroxy-flavanonein 80 ml. absolute ether and ml. absolute tetrahydrofuran are added,dropwise, to a suspension of 0.4 g. lithium alu- 5 minum hydride in 40ml. absolute ether, this being done within 30 minutes. After boiling forhalf-hour, the excess hydride is decomposed with ethyl acetate, andsubsequently mixed with very'dilute hydrochloric acid.

the ether is evaporated. There is obtained 4,4-dihydroxy-6,3f-dimethoxy-flavane having a melting point of 146'148.

In an analogous manner, the following compounds 1 are Produced:6-rnethoxy-4-isobutoxy-flavane 4'hydroxy'6'methoiy'3 4 'methylenedloxy'6-methoxy-4-(Z-dimethylaminoethbxy)-flavan fl n -P2 4 I 6-methoxy-4'-(3-dimethylaminopropoxy)-flavane y .lsoamyloxy' 6-methoxy-3 ,4'-methylenedioxy-fiavane flavane, P I 206-methoxy-3',4'-ethylenedioxy-flavane 3-methyl-4,6-dihydroxy-4-methoxy-flavane, m.p. 3 methyl 6 methoxy 3,,4, ethylendioxy flavane2220-2230 3-methyl-6-methoxy-3',4'-methylenedioxy-flavane 3-rnethyl-4,tgdihydroxy-4-1soamyloxy-flavane, m.p. 3 methyl 6 meth0Xy 3 34,propylenedioxy flavane 1629-163 v3-methyl-6-rnethoxy-3'methoxy-4'-isoamyloxy-4,6-dihydroxy-3',4-d1methoxy-flavane, mp. 25 flavane v 2l32144,6-dihydroxy-3-methoxy-4'isoamyloxy-flavane 3 methoxy 3 methoxy 4sobutoxy 4-hydroxy-6,3 '-dimethoxy-4 '-isoamyloxy-flavane 3 methyl 6,3,4 trimethoxy flavane 4-hydroxy-6,3 '-dimethoxy-4 '-isobutoxy-flavane 3o3 methyl 6 hydroxy 4,methoxyflavane ll y' "dimethoxy'46-hydroxy-4-isopropoxy-flavane dimethylaminoethoxy -f}avane6-hyclroxy-4'-isoamyloxy-flavane 4-hydroxy-6-methoxy-3 ,4-ethylened1oxy-flavane 6 formyloxy 4 3 dimethylaminopropoxy flavane -m PEXAMPLE 29 EXAMPLE 26 4 Y 2.6 g. 6,4'-dimethoxy-flavanone arehydrogenated A i ture of 1 g, 6-methoxy-4-isobutoxy-flavanone withplatinum dioxide, in 250ml. absolute dioxane, at and 0.3 g, sodiumborohydride' in 30' ml. ethanol is r t mperature and normal pressure toform 4- stirred for 10 hours at room temperature, is thereafterhydroxy-6,4'-dimethoxy-flavane: m.p. l48l50" (from acidified with alittle acetic acid and is concentrated 40 ethanol).

under vacuum. The 4-hydroxy-6-methoxy-4'-isobutox- In an analogousmanner, the following compounds y-flavane which precipitates during thisprocess is can be hydrogenated:

recrystallized out of methanol. 6-hydroxy-4-methoxy-flavane to4,6-dihydroxy-4'- In an analogous manner, the following compoundsmethoxy-flavane, m.p. 183-l84 can be produced.6-hydroxy-4'-isoamyloxy-flavanone to 4,6-dihydroxy yyp py-4'-isoamyloxy-flavane, m.p. l62-l634-hydroxy-6-'methoxy-4-isoamyloxy-flavane 4-hydroxy-6-methoxy-4'-(2-dimethylaminoethoxy)- EXAMPLE flavane Ice cold tetrahydrofuran issaturated with diborane, 4-hydroxy-6-methoxy-4'-(3-dirnethylaminopropoxthen mixed with 1.5 g.6,3'-dimethoxy-4-ethoxyy)flavane flavone. The mixture is allowed tostand for 24 hours at room temperature. The excess diborane is destroyedby EXAMPLE the addition of 3 ml. acetic acid and the solvent is 1 g.6,3',4'- trimethoxyflavanone add aluminum distilled off. The residue ismixed with water, is examalgam (from 3 g, aluminum foil) are boiled for6 tracted with ether, and is washed with an aqueous sodihour-S in 100 mL80 percent ethanol) The catalyst is um bicarbonate solution. From theether solution there tered off and the solution is concentrated under isobtained y' y7 which s vacuum, the 4 hydroxy 6,3qflmmethoxvtlavzhle thenrecrystallized from benzene.

being grystamzed out fthi Solution In an analogous manner, the followingcompounds Analogously, other 4-hydroxy-flavanes are obtainaare t f rble, for example, the 4-hydroxy-6-methoxy-4'- ,4 'lmethoxy-flavane 6,3dimethoxy-4 2-dimethylaminoethoxy )-flavane EXAMPLE 28. 6,3-dirnethoxy-4-( 3-dimethylaminopropoxy)- -A solution of 1.5 g.6-methoxy-4'-isoamyloxyn flg'yane flavanone in.2 ml. ethane dithiol and2 ml boron MPLE 3I. trifluoride etherate is allowed to stand for lminutes at 2 g. 6-hydroxy-4-methoxy-2-flavene are hydrogenated in thepresence of 500 mg. Raney-nickel in ml. ethanol. After absorption of 1mol hydrogen, the catalyst is filtered off and the solvent is removedunder reduced pressure, 6-hydroxy-4-methoxy-flavane being obtained.

In an analogous manner, the following compounds can be obtained:

6-( Z-dimethylaminoethoxy )-3 ,4 -di-n-propoxyflavane 6-hydroxy-32-methylethylaminoethoxy )-fiavane6-hydroxy-3-(3-methylethylaminopropoxy)-flavane 6-hydroxy-4-sec.butoxy-flavane 6-hydroxy-4'-n-butoxy-flavane Analogously,3,4'-dimethoxy-6-hydroxy-3-flavene (produced from the correspondingflavylium chloride with lithium aluminum hydride).is hydrogenated toform 3,4 dimethoxy-6-hydroxy-flavane. Likewise, the following compoundsare obtainable from the corresponding 3-flavenes:

3-methoxy-6-hydroxy-4-n-amyloxy-flavane 3-methoxy-6-hydroxy-42-methylethylaminoethoxy)-flavane3-hydroxy-4-'-methoxy-flavane-6-oxy-acetic acid.

EXAMPLE 32.

2,4 g. 3-methyl-4-hydroxy-6-tetrahydropyranyloxy- 4'-ethoxy-flavane isdissolved in 100 ml. dioxane, is mixed with 1.2 g. palladium chloride,and hydrogenated at room temperature. After the calculated quantity ofhydrogen has been absorbed, the catalyst is filtered off, the dioxanesolution is concentrated under reduced pressure, diluted with water and,for removing the remaining dioxane, is again concentrated. The crudeproduct is recrystallized from ethanol,3-methyl-6-tetrahydropyranyloxy-4-ethoxyfiavane being obtained.

Analogously, 4-hydroxy-6-valeryloxy-4 -(3-diethylaminopropoxy)-2-flavene is hydrogenated to form6-valeryloxy-4-(3-diethylaminopropoxy)- flavane.

Analogously, the following compounds are obtainable from thecorresponding 4-hydroxy-flavanes or 4- hydroxy-2-flavenes:

3 -methyl-6-butyryloxy-4 -methoxy-flavane 3 -methyl-6-isobutyryloxy-4'-methoxy-flavane 3-rnethyl6-ethoxy-4'-isoamyloxy-flavane 6-(2-methylethylaminoethoxy)-4 3 methylethylaminopropoxy)-f1avane6-hydroxy-3',4-propylenedioxy-flavane EXAMPLE 3 3.

2 g. 6-n-butoxy-4-(2-diethylaminoethoxy)-flavonol are hydrogenated with0.5 g. Raney-nickel in 30 ml. ethanol at 120 under a pressure of 40atmospheres of hydrogen. After cooling, the catalyst is filtered off andthe filtrate is concentrated until the3-hydroxy-6-n-butoxy-4-(2-diethylaminoethoxy)-flavane is crystallized.

In an analogous manner, the following compounds can be created:

3,4-dihydroxy-6-methoxy-flavane3-hydroxy-6-methoxy-4'-isoamyloxy-flavane 3-hydroxy.-6sec.butoxy-3-(2-dirnethylaminoethox- 65 g y )-flavane EXAMPLE 34.

benzoyl peroxide are dissolved in 40 ml. chloroform and added to aboiling solution of 3 g N-bromo-succinimide in 30 ml. chloroform. After4 hours boiling, the chloroform is distilled off, the residue isdissolved in ml. ethanol, mixed with 50 ml. 20 percent aqueous potassiumcarbonate solution, and boiled for 30 minutes. Then, the solution isweakly acidified (pH 6.5), the ethanol is distilled off, the residue ismixed with water and extracted with chloroform. After the solvent isevaporated, the obtained 6-hydroxy-4- isoamyloxy-flavone isrecrystallized out of ethanol.

In the same manner, the following compounds produced:

6-hydroxy-4 -n-propoxy-flavone 6-hydroxy-4-isopropoxy-flav0ne6-hydroxy-4 '-n-butoxy-flavone 6-hydroxy-4'-isobutoxy-flavone6-hydroxy-4'-n-hexyloxy-flavone' 6-hydroxy-4'-isohexyloxy-flavone6-hydroxy-4'-(Z-dimethylaminoethoxy)-flavone6-hydroxy-4'-(3-dimethylaminopropoxy)-flavone If the free6-hydroxy-flavones are heated with acetic anhydride in pyridine for onehour under reflux conditions, the corresponding 6-acetoxy compounds areobtained. Analogously, the corresponding 6-propionoxy, 6-butyroxy,6-valeroyloxy, and 6-caproyloxy compounds are obtainable.

EXAMPLE 35.

Under cooling, 10 ml, 15 percent hydrogen peroxide and 15 ml, 16 percentsolution of sodium hydroxide are added to a solution. of 1.4 g.6-methoxy-4'-(2- dimethylaminoethoxy)-flavanone in ml. methanol. After 4hours stirring and standing overnight at room temperature, the mixtureis acidified with dilute sulfuric acid and the precipitate is removed bysuction. The alcoholic solution of the substance is placed upon a silicagel column, and the latter is eluted with a mixture of a dilute solutionof sodium hydroxide/methanol. The eluted substance is concentrated,mixed with the same volume of water, and extracted with chloroform. Theorganic phase is washed, dried with sodium sulfate, the solvent isdistilled off, and the residue is crystallized out of ethanol, pure6'-methoxy-4'-(2- dimethylaminoethoxy)-flavenol being obtained, m.p.197.

In place of the methanol, it is also possible to employ a mixture ofethanol and dioxane.

are

Analogously, the following compounds are produced:

6-methoxy-4'-hydroxy-flavenol, m.p. 27027 1 6,3',4-trimethoxy-flavonol,m.p. 188189 6-methoxy-3 ,4-methylenedioxy-flavonol, m.p.

21 1-212 6-methoxy-4'-(3-dimethylaminopropoxy)-flavonol,

m.p. 137138 6-methoxy-4'-(2-diethylaminoethoxy)-flavonol6-methoxy-4-(2-pyrrolidinoethoxy)-flavonol6-methoxy-4-(2-piperidinoethoxy-flavonol6-methoxy-4-(2-morpholinoethoxy)-flavonol6-acetamido-4'-methoxy-flavonol 6-acetamido-4-ethoxy-flavonol6-acetamido-4'-isopropoxy-fiavonol 6-acetamido-4-isobutoxy-flavonol6-acetamido-4-isoamyloxy-fiavonol Y (out of ethanol) by treating4'-methoxy-flavanone-6- oxy acetic acid ethyl ester with hydrogenperoxide in an aqueous/methanolic solution of sodium hydroxide at roomtemperature. Under the influence of the alkaline reaction medium, avsaponification of the ester group takes place simultaneously.

EXAMPLE 36.

A solution of 3.6 g. 3-bromo-6-methoxy-4- isoamyloxy-flavanone in 45 ml.ethanol is mixed with 20 ml. of a 10 percent potassium hydroxidesolution and stirred for 20 minutes at room temperature. The mixture isdiluted with water, the separated 6-methoxy- 4"-isoamyloxy-flavone isfiltered off, washed with water, and recrystallized from ethanol.

In an analogous manner, other 6-alkoxy flavones are obtainable.

EXAMPLE 37.

A solution of 3.4 g. 6-methoxy-4'-isoamyloxyflavanone in 150ml. ether isslowly mixed alternately with 7.7 g. pentyl nitrite and 2 ml.concentrated hydrochloric acid, is allowed to stand overnight at and isthen stirred into 100 ml. 2 percent solution of sodium hydroxide. Theaqueous layer is acidified with acetic acid and extracted with benzene.The crude isonitrosoketone obtained after the benzene is evaporated isdissolved in 40 ml. acetic acid and a solution of 3.1 g. stannouschloride in 6.2 ml, concentrated hydrochloric acid is added thereto. Theprecipitate which separated after the mixture was allowed to stand for alonger period of time, is filtered off, washed with a little aceticacid, and the 3-amino compound is freed by stirring for 40 minutes with40 ml. 10 percent solution of sodium hydroxide. The mixture is extractedwith chloroform and theextract is washed with water and dried withsodium sulfate. The 3-amino-6-methoxy-4'- isoamyloxy-flavone remainingafter the chloroform has been removed is recrystallized out of ethanol.

Analogously, the following compounds producedi3-amino-6,4'wdimethoxy-flavone 3-amino-6-methoxy-4ethoxy-flavone3-arnino-6-methoxy-4'-isopropoxy-flavone3-amino-6-methoxy-4.-isobutoxy-flavone 3-amino-6-methoxy-42-dimethylaminoethoxy)- are flavone 3-amino-6-methoxy-43-dimethyliuninopropoxy flavone EXAMPLE 38.

1.5 g. 6-acetamido-4-isobutoxy-flavanone and 4.5 g. chloranil areboiled, under stirring, in ml. tert. butanol for 3 hours. The excesschloranil is filtered off, the filtrate is concentrated to dryness, theresidue is taken up in chloroform and the organic phase is washed withwater, potassium-carbonate solution, and again with water. After thesolvent has been driven off, the 6- acetamido-4'-isobutoxy-flavone isderived from the dried extract.

Analogously, produced:

6-acetamido-4 #methoxy-flavone 6-acetamido-4'-ethoxy-flavone6-acetamido-4'-isopropoxy-flavone 6-acetamido-4-isoamyloxy-flavone6-acetamido-4 Z-dimethylaminoethoxy )-flavone 6-acetamido-4 3-dimethylaminopropoxy )-flavone By 8 hours boiling of these substanceswith 10 methanolic hydrochloric acid, the hydrochlorides of thecorresponding G-amino compounds are produced.

the following compounds are EXAMPLE 39.

l g. 6-isonitroso-6-methoxy-4-isoamyloxy-flavanone (produced as inExample 37) is dissolved in glacial acetic acid. 10 percent sulfuricacid is added until the solution becomes cloudy. Then, heating on thesteam bath is carried out for 30 minutes, and subsequently, the solutionis cooled to room temperature. After being allowed to stand overnight,the separated 6-methoxy-4' -isoamyloxy-flavanol is filtered off andrecrystallized out of ethanol; m.p. 144-l45.

EXAMPLE 40.

0.45 g. 3-hydroxy-6-methoxy-4'-isoarnyloxyflavanone and l g. cinnamicacid (phenyl acrylic acid) are heated to boiling in 20 ml. water with0.15 g 10 percent palladium charcoal, under stirring for 20 minutes.After cooling, ethanol is added, the mixture is heated and filtered inthe warm state. The filtrate is mixed with aqueous sodium bicarbonatesolution, the separated 6- methoxy-4'-isoamyloxy-flavanol is filteredoff, washed with water, and recrystallized from ethanol; m.p. 144145.

EXAMPLE 41 2 g. 3-methyl-6-tetrahydropyranyloxy-4'-ethoxyflavane areboiled in 50 ml. 5 percent aqueous ethanolic hydrochloric acid for 2hours under reflux conditions. After cooling, the mixture is worked upwith chloroform and water, 3-methyl-6-hydroxy-4'-ethoxyflavane beingobtained.

Analogously, 3-methyl-6-hydroxy-4'-methoxyflavane (melting point 142,from ether) and 3-methyl- 6-hydroxy-4'-isoamyloxy-flavane can beobtained.

EXAMPLE 42.

A solution of 2.5 g. magnesium iodide is added to a 11 as mixture i mi eilats. sy wia s d the precipitate is filtered off, and is dissolved inboiling water. After extracting with hot benzene, the aqueous phase isseparated and cooled, 3-methyl-6,4-dihydroxy-flavone being separated.

EXAMPLE 43.

l g. 6-methoxy-4'-benzyloxy-flavanone is hydrogenated in 50 ml. ethylacetate saturated with hydrochloric acid, this hydrogenation beingcarried out 10 on 5 percent palladium charcoal at 35, until thecalculated hydrogen quantity has been absorbed. The catalyst is filteredoff, the solvent is removed, and the obtained6-methoxy-4'-hydroxy-flavanone is recrystallized from methanol; m.p.178l79.

EXAMPLE 44.

EXAMPLE 45.

2.5 g. 6,4-dihydroxy-flavone (obtained by reaction of2-hydroxy-5-benzyloxyacetophenone with pbenzyloxy benzoic acid chloride,rearrangement of the obtained ester with-potassium hydroxide inpyridine, and ring closure with concentrated hydrochloric acid/glacialacetic acid with simultaneous splitting off of ether), 4.8 g.isopropylbromide, and 13.2 g. anhydrous potassium carbonate are reactedin 30 ml dry acetone, as described in Example 13, and the reactionmixture is worked up. As end product, 6,4-diisopropoxy-flavone isisolated.

Analogously, the following compounds are obtained by reaction with thecorresponding chlorides or bromides:

6,4 '-di-sec. butoxy-flavone v 6,4'-di-n-amyloxy-flavone6,4-di-isoamyloxy-flavone 6,4'-di-nrhexyloxy-flavone6,4'-di-isohexyloxy-flavone 6,4'-di-heptyloxy-flavone6,4'-bis-(2-dimethylaminoethoxy)-flavone6,4-bis-(3-dimethylaminopropoxy)-flavone EXAMPLE 46 1.4 g,6-hydroxy-3,4-methylenedioxy-flavanone, 0.9 g, bromoacetic acid ethylester (or chloroacetic acid ethyl ester) and 0.7 g, potassium carbonateare boiled for 24 hours in ml, absolute acetone under reflux conditions.The mixture is mixed with water and extracted with chloroform. From theextract, 3,4'- methylene-dioxy-flavanone-6-oxyacetic acid ethyl ester isobtained which melts, after recrystallization from ethanol, at 136138.

Analogously, the following compounds can be produced:

4'-methoxy-flavanone-6-oxyacetic acid ethyl ester,

m.p. 4'-isoamyloxy-flavanone-6oxyacetic acid ethyl ester,

m.p. 9293 4'-dimethylamino-flavanone-6-oxyacetic acid ethyl ester, mp.15 l152 3-methyl-4'-methoxy-flavanone-6oxyacetic ethyl ester, m.p. 92-933-methyl-4'-dimethylamino-flavanone--oxyacetic acid ethyl ester, m.p.137-138 3,4'-dimethoxy-fiavanone-6-oxyacetic acid ethyl ester, m.p. -1313-methyl-3',4'-dimethoxy-flavanone-6-oxyacetic acid ethyl ester, m.p.10010l 3-methyl-3 ",4-methylenedioxy-flavanone-6oxyacetic acid ethylester, m.p. 1 14-1 15 4'-ethoxy-flavanone-6-oxyacetic acid ethyl ester4-isopropoxy-flavanone-6-oxyacetic acid ethyl ester4-isobutoxy-flavanone-6oxyacetic acid ethyl ester4'-isoamyloxy-flavanone-6-oxyacetic acid ethyl ester3-methyl-3'-methoxy-4'-ethoxy-flavanone-6oxyacetic acid ethyl ester v3-methyl-3-methoxy-4'-isopropoxy-fiavanone-6-oxyacetic acid ethyl ester3-methyl-3'-methoxy-4-isobutoxy-flavanone-6-ox yacetic acid ethyl esterI 3 -methyl- 3 -methoxy-4 -isoamyloxy-flavanone-6-oxyacetic acid ethylester 3-methyl-3'-methoxy-4'-(2-dimethylaminoethoxy)-flavanone-6-oxyacetic acid ethyl ester3-methyl-3-methoxy-4-(2-dimethylaminoethoxy)- flavanone-6-oxyacetic acidethyl ester 3-methyl-3 '-methoxy-43-dimethylaminopropoxy)-flavanone-6-oxyacetic acid ethyl ester3-methyl-3 ,4'-methylenedioxy-flavanone-6-oxyacetic acid ethyl ester3-methyl-3 ,4 ethyl enedioxy-flavanone-6-oxyacetic acid ethyl ester3-methyl-3,4-propylenedioxy-flavanone-6-ox yacetic acid ethyl ester aswell as 4-methoxy-, 4'-ethoxy-, 4-isopropoxy-, 4-n-butox-' yand4-isoamyloxy-flavane-6-oxyacetic acid ethyl ester, 4-methoxy (mp.4'-ethoxy-, 4' -isopropoxy-, 4-isobutoxyand 4'-isoamyloxy-flavone6-oxyacetic acid ethyl ester acid3,4'-ethylenedioxy-flavanone-6-oxyacetic acid ethyl ester 3 '-methoxy-4-isoamyloxy-fiavanone-6-oxyacetic acid ethyl ester 3 '-methoxy-42-dimethylamino ethoxy )'-flavanone- 6-oxyacetic acid ethyl ester Afterboiling the obtained esters with 2n ethanolic potassium hydroxidesolution for 1 hour, there is obtained, after acidifying, thecorresponding flavanone-6- oxyacetic acids, flavane-6-oxyacetic acids,or flavone- 6-oxyacetic acids.

If the bromoacetic acid ethyl ester is replaced by chloroor bromoaceticacid methyl ester, analogously the corresponding flavane-6-oxyaceticacid methyl esters are obtained.

If other a-chloroand/or a-bromo-fatty acid esters are used, thecorresponding a-(flavane-6-oxy)-fatty

2. A pharmaceutical composition as defined by claim 1, wherein R3 ishydroxy.
 3. A pharmaceutical composition as defined by claim 1, whereinR1 OH; acyloxy of one to six carbon atoms, the acyl portion beingderived from a carboxylic acid; alkoxy of one to six carbon atoms; oralkoxy of one to six carbon atoms in the alkoxy chain substituted bycarbalkoxy of two to nine carbon atoms or by pyrrolidinocarbonyl; R2alkoxy of one to six carbon atoms; or, together with R5, methylenedioxy;R3 alkyl of one to three carbon atoms; or alkoxy of one to three carbonatoms; R4 H2 or O; R5 H or OCH3 or, together with R2, methylenedioxy;and wherein the 2,3-position of said compound is optionally connected bya double bond.
 4. A pharmaceutical composition as defined by claim 1,wherein said compound is 6,3'',4''-trimethoxy flavonol.
 5. A process oflowering the level of cholesterol in the blood of mammals, which processcomprises administering an effective cholesterol-level-lowering amountof a compound selected from the group consisting of a flavanoid, an acidaddition salt thereof, and a quaternary ammonium derivative thereof,said flavanoid having the formula wherein R1 and R2 are each selectedfrom the group consisting of OH; alkoxy of one to 10 carbon atoms;tetrahydropyranyl-(2)-oxy; acyloxy of 1-6 carbon atoms wherein the acylportion is derived from a hydrocarbon carboxylic acid; NO2; NH2;alkylated NH2 having one to eight carbon atoms; acylamino of two to sixcarbon atoms wherein the acyl portion is derived from a hydrocarboncarboxylic acid; an alkoxy group of one to 10 carbon atoms in the alkoxychain substituted by a member of the group consisting of phenyl; amino;alkylated amino of one to nine carbon atoms; pyrrolidino; carboxy;carbalkoxy of two to nine carbon atoms; cyano; carboxamido;dialkylcarboxamido of three to nine carbon atoms; pyrrolidinocarbonyl;and (2-hydroxyethylamino)-carbonyl; R2 together with R5 is selected fromthe group consisting of methylene dioxy, ethylene dioxy, and propylenedioxy; R3 is selected from the group consisting of H; OH; alkyl of 1-3carbon atoms; alkoxy of one to three carbon atoms; NH2; Cl; Br; and I;R4 is selected from the group consisting of O; H,OH; H,H; and H, NH2; R5is selected from the group consisting of H and R1; and wherein the2,3-position of said flavanoid is optionally connected by a double bond.6. A process as defined by claim 5, wherein R3 is hydroxy.
 7. A processas defined by claim 5, wherein R1 OH; acyloxy of one to six carbonatoms, the acyl portion being derived from a carboxylic acid; Alkoxy ofone to six carbon atoms; or alkoxy of one to six carbon atoms in thealkoxy chain substituted by carbalkoxy of 2-9 carbon atoms or bypyrrolidinocarbonyl; R2 alkoxy of one to six carbon atoms; or, togetherwith R5, methylenedioxy; R3 alkyl of one to three carbon atoms; oralkoxy of one to three carbon atoms; R4 H2 or O; R5 H or OCH3 or,together with R2, methylenedioxy; and wherein the 2,3-position of saidcompound is optionally connected by a double bond.
 8. A process asdefined by claim 5, wherein R4 is H2.
 9. A process as defined by claim8, wherein R1 is OH or acyloxy of one to six carbon atoms, the acylportion being derived from a carboxylic acid; R2 is methoxy; R3 is alkylor alkoxy of one to three carbon atoms; R4 is H2 or O; and R5 is H. 10.A process as defined by claim 5, wherein said compound is 6,3'',4''-trimethoxy flavonol.